Benzamidine derivative

ABSTRACT

Benzamidine derivatives of the following formula, analogs thereof and pharmaceutically acceptable salts thereof are provided. These compounds have an effect of inhibiting activated blood-coagulation factor X, and they are useful as agents for preventing or treating various diseases caused by thrombi or emboli.

The present application is a Continuation Application of U.S. Ser. No.09/731,729, filed Dec. 8, 2000, allowed, which in turn is a ContinuationApplication of PCT/JP99/03055, filed Jun. 8, 1999.

BACKGROUND OF THE INVENTION

The present invention relates to new benzamidine derivatives which canbe orally administrated to exhibit a strong anticoagulant effect byreversibly inhibiting activated blood-coagulation factor X;anticoagulants containing them as active ingredients; and agents forpreventing or treating diseases caused by thrombi or emboli. Thesediseases include, for example, cerebrovascular disorders such ascerebral infarction, cerebral thrombosis, cerebral embolism, transientischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm);ischemic heart diseases such as acute and chronic myocardial infarction,unstable angina and coronary thrombolysis; pulmonary vascular disorderssuch as pulmonary infarction and pulmonary embolism; peripheralobliteration; deep vein thrombosis; disseminated intravascularcoagulation syndrome; thrombus formation after an artificial bloodvessel-forming operation or artificial valve substitution; re-occlusionand re-stenosis after a coronary bypass-forming operation; re-occlusionand re-stenosis after reconstructive operation for the blood circulationsuch as percutaneous transluminal coronary angioplasty (PTCA) orpercutaneous transluminal coronary recanalization (PTCR); and thrombusformation in the course of the extracorporeal circulation.

As the habit of life is being westernized and people of advanced agesare increasing in Japan, thrombotic and embolismic patients such asthose suffering from myocardial infarction, cerebral thrombosis andperipheral thrombosis are increasing in number year by year, and thetreatment of patients with these diseases is becoming more and moreimportant in the society. Anticoagulation treatment is included in theinternal treatments for the remedy and prevention of thrombosis, likeradiotherapy and antithrombocytic therapy.

Antithrombins were developed as thrombus-formation inhibitors in theprior art. However, it has been known that since thrombin not onlycontrols the activation of fibrinogen to form fibrin, which is the laststep of the coagulation reaction, but also deeply relates to theactivation and coagulation of blood platelets, the inhibition of theaction of thrombin causes a danger of causing hemorrhage. In addition,when antithrombins are orally administered, the bioavailability thereofis low. At present, no antithrombin which can be orally administered isavailable on the market.

Since the activated blood coagulation factor X is positioned at thejuncture of an exogenous coagulation cascade reaction and an endogenouscoagulation cascade reaction and in the upstream of thrombin, it ispossible to inhibit the coagulation system more efficiently andspecifically, than the thrombin inhibition, by inhibiting the factor X(THROMBOSIS RESEARCH, Vol. 19, pages 339 to 349; 1980).

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide compounds having anexcellent effect of inhibiting the effect of activated blood coagulationfactor X.

Another object of the present invention is to provide compounds havingan effect of specifically inhibiting the effect of activated bloodcoagulation factor X, which can be orally administered.

Still another object of the present invention is to provide ablood-coagulation inhibitor or an agent for preventing or treatingthrombosis of embolism, which contains one of the above-describedcompounds.

After intensive investigations made under these circumstances, theinventors have found that specified new benzamidine derivatives have anexcellent effect of inhibiting activated blood coagulation factor X andare usable for preventing and treating various diseases caused bythrombi and emboli. The present invention has been completed on thebasis of this finding.

Namely, the present invention provides benzamidine derivatives offollowing general formula (1-1), (1-2), (1-3) or (1-4) orpharmaceutically acceptable salts thereof, and blood coagulationinhibitors containing them as the active ingredients:

In general formula (1-1), L represents an organic group of followingformulae (2) to (5):

In formulae (2), (3) and (5), W represents hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, an aryl group having 4 to 10 carbon atoms oran aralkyl group having 5 to 12 carbon atoms, one of D and D′ in formula(3) represents a bond to Y in general formula (1-1) and the otherrepresents hydrogen atom.

In formula (2), X represents hydrogen atom, carboxyl group, analkoxycarbonyl group having 1 to 3 carbon atoms, an alkyl group having 1to 3 carbon atoms which may have a substituent(s) or benzimidoyl groupwhich may have a substituent(s). The substituent(s) is (are) selectedfrom among carboxyl group, alkoxycarbonyl groups having 2 to 8 carbonatoms, alkylsulfonyloxy groups having 1 to 6 carbon atoms, piperidyloxygroup, iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms,alkoxycarbonylpiperidyloxy groups having 7 to 14 carbon atoms,piperidylalkyl groups having 6 to 8 carbon atoms,iminoalkylpiperidylalkyl groups having 7 to 11 carbon atoms,alkoxycarbonylpiperidylalkyl groups having 8 to 15 carbon atoms,pyrrolidinyloxy group, iminoallcylpyrrolidinyloxy groups having 5 to 9carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbonatoms, amidino group, mono- or dialkylamidino groups having 2 to 7carbon atoms, hydroxyl group, halogeno groups, indolyl group and alkylgroups having 1 to 3 carbon atoms. In formula (2), X and W may be bondedtogether to form a ring and, in this case, —W—X— represents ethylenegroup, trimethylene group or tetramethylene group.

When L is an organic group of any of formulae (2) to (4), V₁ representshydrogen atom, benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl,piperazinecarbonyl, cinnamoyl, piperidinecarbonyl,4-methylthiazole-5-carbonyl, phenylacetyl, phenylthiocarbonyl orbenzimidoyl group which may have a substituent(s) or an alkanesulfonylgroup having 1 to 6 carbon atoms, which may have a substituent(s). WhenL is an organic group of formula (5), V₁ represents an aryl group having4 to 10 carbon atoms, which may have a substituent(s).

When L is an organic group of any of formulae (2) to (5) and V₁ has asubstituent, the substituent is selected from among carboxyl group,alkoxycarbonyl groups having 2 to 7 carbon atoms, carbamoyl group, mono-or dialkylcarbamoyl groups having 2 to 7 carbon atoms, amidino group,mono- or dialkylamidino groups having 2 to 7 carbon atoms, acyl groupshaving 1 to 8 carbon atoms, halogeno groups, amino group, mono- ordialkylamino groups having 1 to 6 carbon atoms, arylamino groups having4 to 6 carbon atoms, alkoxycarbonylamino groups having 2 to 7 carbonatoms, aminoalkyl groups having 1 to 3 carbon atoms, mono- ordialkylaminoalkyl groups having 2 to 7 carbon atoms,N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon atoms,piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbonatoms, alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms,pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbonatoms, hydroxycarbonylalkyl groups having 2 to 7 carbon atoms,alkoxycarbonylalkyl groups having 3 to 8 carbon atoms,hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms,alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl groupshaving 4 to 10 carbon atoms, arylalkenyl groups having 6 to 12 carbonatoms, alkoxyl groups having 1 to 10 carbon atoms, nitro group,trifluoromethyl group, alkyl groups having 3 to 8 carbon atoms,arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl groups having5 to 12 carbon atoms, piperazinecarbonyl group,iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms,piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups having 6to 9 carbon atoms, piperidylalkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms,piperidylidenealkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylinealkyl groups having 8 to 12 carbon atoms,guanidino group, dialkylguanidino groups having 3 to 5 carbon atoms,phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atoms,monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms,trialkylamidino groups having 4 to 7 carbon atoms, dialkoxybenzoylgroups having 9 to 13 carbon atoms, 1-alkylpyridinio groups having 6 to9 carbon atoms and groups of the following formulae:

In formulae (6) and (7), A represents a halogeno group, and in formulae(8) and (9), B represents hydrogen atom, an alkyl group having 1 to 6carbon atoms, a halogeno group or amino group.

Y represents any of following formulae (10) to (16):

In formulae (10) and (11), n represents an integer of 0 to 2. In formula(16), R¹ represents a hydrogen atom, a hydroxycarbonylalkyl group having2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8 carbonatoms or a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms.

Z₁ represents a group of any of following formulae (17) to (24):

In formulae (17), (19), (21) and (23), m represents an integer of 0 to3. In formulae (17), (18) and (24), R² represents hydroxyl group, analkoxyl group having 1 to 5 carbon atoms, trifluoromethyl group, aminogroup or a mono- or dialkylamino group having 1 to 6 carbon atoms. Informula (19), R³ represents hydrogen atom, an alkyl group having 1 to 6carbon atoms or acetyl group. In formulae (20) to (230), R⁴ representshydrogen atom or an alkyl group having 1 to 6 carbon atoms. In formulae(22) and (23), R⁵ represents hydrogen atom or an alkyl group having 1 to6 carbon atoms. In formula (24), R⁶ represents a halogeno group:

wherein Z₁₁ represents carboxyethyl group, ethoxycarbonylethyl group,hydroxymethyl group or hydroxypropyl group, and E represents anoil-soluble organic group

In general formula (1-3), L represents an organic group of any offormulae (2) to (5) in above general formula (1-1). In formulae (2), (3)and (5), W is as defined in above general formula (1-1). In generalformula (2), X is as defined in above general formula (1-1),

When L represents an organic group of formulae (2) to (4), V₂ representsbenzoyl, benzenesulfonyl, 2-naphthalenesulfonyl, cinnamoyl,piperidinecarbonyl, phenylacetyl, phenylthiocarbonyl or benzimidoyl

In general formula (1-4), L₂ represents an organic group represented byformulae (2) to (4) in general formula (1-1), and W in formulae (2) and(3) and X in formula (2) are each as defined in above general formula(1-1),

when L₂ represents an organic group of formulae (2) to (4), V₁ is asdefined in above general formula (1-1), and when V₁ has asubstituent(s), the substituent is as defined in above general formula(1-1), and

Y₂ is any of formulae (10) and (11) in above general formula (1-1), andR⁸ represents hydrogen atom, an alkyl group having 1 to 6 carbon atomsor acetyl group.

BEST MODE FOR CARRYING OUT THE INVENTION

The alkyl groups in the present invention may be branched or have aring. For example, the alkyl groups include cyclohexylmethyl group orthe like. The term “aryl” herein involves not only aromatic cyclichydrocarbon groups but also aromatic heterocyclic groups having 1 to 3hetero-atoms selected from among O, N and S. Examples of the aryl groupsinclude phenyl, pyridyl, imidazolyl and pyrrolyl groups. An group havinga substituent. When L is an organic group of formula (5), V₂ representsan aryl group having 4 to 10 carbon atoms, which may have a substituent.

When L represents an organic group of formulae (2) to (5), thesubstituents of V₂ include trialkylamidino groups having 4 to 7 carbonatoms, dialkoxybenzoyl groups having 9 to 13 carbon atoms and1-alkylpyridinio groups having 6 to 9 carbon atoms.

Y is represented by any of formulae (10) to (16) in above generalformula (1-1), wherein n represents an integer of 1 or 2, and R¹ is asdefined above.

Z₂ represents hydrogen atom, an alkyl group having 1 to 6 carbon atoms,a halogeno group or a group of following formula (13-2):

In formula (13-2), R₂₂ represents carboxyl group or an alkoxycarbonylgroup having 2 to 5 carbon atoms. example of the arylalkenyl groups is2-(4-pyridyl)vinyl group. Dialkylamidino groups includeN,N-dialkylamidino groups and N,N′-dialkylamidino groups. The two alkylgroups in the dialkylcarbamoyl groups, dialkylamidino groups,dialkylamino groups, dialkylaminoalkyl groups, dialkylaminosulfonylgroups and dialkylguanidino groups may be bonded together to form aring. In those groups, one of CH₂'s may be replaced with O, NH or S. Forexample, dialkylcarbamoyl groups include, for example,1-pyrrolidinecarbonyl group; dialkylamidino groups include, for example,2-imidazoline-2-yl group and (pyrrolidine-1-yl)(imino)methyl group; anddialkylguanidino groups include, for example, imidazoline-2-amino group.The acyl groups include not only alkylcarbonyl groups but alsoarylcarbonyl groups. For example, the acyl groups having 1 to 8 carbonatoms include benzoyl group. The alkoxyl groups include, for example,cyclohexyloxy group and phenoxyl group. The alkoxycarbonyl groupsinclude benzyloxycarbonyl group, etc. Preferred 1-alkylpyridinio groupshaving 6 to 9 carbon atoms are all of those having 6 carbon atoms or 7to 9 carbon atoms.

The compounds of the present invention may have an asymmetric carbonatom. These compounds include mixtures of various stereoisomers such asgeometrical isomers, tautomers and optical isomers, and those isolatedtherefrom. The amidino group in the compounds of the present inventionmay be replaced with a suitable substituent which can be changed intothe amidino group in vivo. For example, hydrogen atom bonded to nitrogenatom having double bond in amidino group bonded to the benzene ring ingeneral formulae (1-1) to (1-4) is replaced with hydroxyl group, analkoxyl group such as ethoxyl group, amino group, carboxyl group, analkoxycarbonyl group such as ethoxycarbonyl group, an alkylsulfonylgroup such as ethylsulfonyl group, carbamoyl group, carbamoyl group inwhich one or two hydrogen atoms are replaced with an alkyl group such asdiethoxycarbamoyl group, formyl group, an acyl group such as acetylgroup or an alkylcarboxyl group such as acetoxyl group.

L in general formula (1-1) is preferably that represented by formulae(2) to (4), more preferably formulae (2) and (4), and particularlyformula (2).

W is preferably hydrogen atom or an alkyl group having 1 to 6 carbonatoms. W is particularly preferably hydrogen atom. X is preferablyhydrogen atom, a carboxyalkyl group having 2 or 3 carbon atoms or analkoxycarbonylalkyl group having 3 to 10 carbon atoms. W is particularlypreferably hydrogen atom, carboxymethyl group or ethoxycarbonylmethylgroup. X is preferably hydrogen atom, carboxyl group, an alkyl grouphaving 1 to 3 carbon atoms, which may have a substituent(s), or benzylgroup which may have a substituent(s). X is particularly preferablyhydrogen atom or an alkyl group having one carbon atom and asubstituent.

When X has a substituent, the substituent is, for example,benzyloxycarbonyl group, carboxyl group, methoxycarbonyl group,ethoxycarbonyl group, ethanesulfonyloxy group, butanesulfonyloxy group,4-piperidyloxy group, 1-acetimidoyl-4-piperidyloxy group,(1-acetimidoyl-4-piperidyl)methyl group, 1-acetimidoyl-3-pyrrolidyloxygroup, isopropyl group, 3-indolyl group or iodine atom. In thesesubstituents, carboxyl group is particularly preferred.

V₁ is preferably benzoyl group which may have a substituent(s),piperidinecarbonyl group which may have a substituent(s) orpyridinecarbonyl group which may have a substituent(s). V₁ is morepreferably benzoyl group having a substituent(s) or piperidinecarbonylgroup having a substituent(s).

When V₁ has a substituent, the substituent is preferably 4-piperydyloxygroup, 1-acetimidoyl-4-piperidyloxy group, 4-pyridyl group,tetrafluoropyridyl group, 3,5-dichloropyridyl group, 6-chloropyridazylgroup, pyridazyl group, 2-chloropyrimidyl group, pyrimidyl group,4-pyridine-4-ylmethyl group or 4-pyridylcarbonyl group. The substituentis more preferably 1-acetimidoyl-4-piperidyloxy group or 4-pyridylgroup. V₁ is particularly preferably either1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)-piperizine-4-carbonyl group.

It is more preferred that Y represents an organic group of formula (10)wherein n is an integer of 1.

Z₁ is preferably a group represented by formula (17), (19), (21) or(23). Z₁ is more preferably carboxyethyl group, ethoxycarbonylethylgroup, sulfoethyl group, phosphonoethyl group, diethoxyphosphorylethylgroup, monoethoxyhydroxyphosphorylethyl group, hydroxymethyl group orhydroxypropyl group. Z₁ is particularly preferably carboxyethyl group,ethoxycarbonylethyl group, hydroxymethyl group or hydroxypropyl group.

In the compounds of general formula (1-1), benzamidine derivatives ofgeneral formula (1-1) wherein L represents an organic group of formula(2), W represents hydrogen atom and X represents any of hydrogen atom,carboxymethyl group and ethoxycarbonylmethyl group, or pharmaceuticallyacceptable salts thereof are preferred.

Benzamidine derivatives of general formula (1-1) wherein Y represents anorganic group of formula (10), and n represents an integer of 1 or 2 orpharmaceutically acceptable salts thereof are preferred.

Preferred compounds are benzamidine derivatives of general formula (1-1)wherein V₁ represents 1-acetimidoyl-4-piperidyloxybenzoyl group,1-(4-pyridyl)-piperidine-4-carbonyl group,1-(2,3,5,6-tetrafluoropyridine-4-yl)-piperidine-4-carbonyl group,1-(3,5-dichloropyridine-4-yl)-piperidine-4-carbonyl group,1-(6-chloropyridazine-3-yl)-piperidine-4-carbonyl group,1-(pyridazine-3-yl)-piperidine-4-carbonyl group,1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group,1-(pyrimidine-4-yl)-piperidine-4-carbonyl group,1-(4-pyridine-4-ylmethyl)-piperidine-4-carbonyl group,1-(4-pyridine-4-carbonyl)-piperidine-4-carbonyl group or4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl group, or pharmaceuticallyacceptable salts thereof.

Preferred compounds are benzamidine derivatives of general formula (1-1)wherein Z₁ represents carboxyethyl group, ethoxycarbonylethyl group,carboxyvinyl group, ethoxycarbonylvinyl group, carbamoylethyl group,carbamoylvinyl group, carboxyl group, ethoxycarbonyl group,methoxycarbonyl group, sulfoethyl group, sulfovinyl group,phosphonovinyl group, diethoxyphosphorylvinyl group,monoethoxyhydroxyphosphorylvinyl group, phosphonoethyl group,diethoxyphosphorylethyl group, monoethoxyhydroxyphosphorylethyl group,hydroxymethyl group, hydroxypropyl group or acetoxymethyl group, orpharmaceutically acceptable salts thereof.

Preferred compounds are benzamidine derivatives of general formula (1-1)wherein Y represents an organic group of formula (10), V₁ represents1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)piperidine-4-carbonyl group and Z₁ represents carboxyethylgroup, ethoxycarbonylethyl group, sulfoethyl group, hydroxymethyl groupor hydroxypropyl group, or pharmaceutically acceptable salts thereof.

Preferred compounds are benzamidine derivatives of general formula (1-1)wherein L represents an organic group of formulae (2) to (4) and Yrepresents an organic group of formulae (10) to (13), orpharmaceutically acceptable salts thereof.

Preferred benzamidine derivatives are those of general formula (1-1)wherein, when L represents an organic group of formulae (2) to (4), V₁represents hydrogen atom, benzoyl, benzenesulfonyl,2-naphthalenesulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl,phenylthiocarbonyl or benzimidoyl group which may have a substituent(s)or an alkanesulfonyl group having 1 to 6 carbon group, which may have asubstituent(s); when L represents an organic group of formula (5), V₁represents an aryl group having 4 to 10 carbon atoms, which may have asubstituent(s);

when L represents an organic group of formulae (2) to (5), thesubstituents of V₁ are carboxyl group, alkoxycarbonyl groups having 2 to7 carbon atoms, carbamoyl group, mono- or dialkylcarbamoyl groups having2 to 7 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms,amidino group, mono- or dialkylamidino groups having 2 to 7 carbonatoms, acyl groups having 1 to 8 carbon atoms, halogeno groups, aminogroup, mono- or dialkylamino groups having 1 to 6 carbon atoms,arylamino groups having 4 to 6 carbon atoms, alkoxycarbonylamino groupshaving 2 to 7 carbon atoms, aminoalkyl groups having 1 to 3 carbonatoms, mono- or dialkylaminoalkyl groups having 2 to 7 carbon atoms,N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon atoms,piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbonatoms, alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms,pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbonatoms, hydroxycarbonylalkyl groups having 2 to 7 carbon atoms,alkoxycarbonylalkyl groups having 3 to 8 carbon atoms,hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms,alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl groupshaving 4 to 10 carbon atoms, arylalkenyl groups having 6 to 12 carbonatoms, alkoxyl groups having 1 to 10 carbon atoms, nitro group,trifluoromethyl group, alkyl groups having 3 to 8 carbon atoms,arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl groups having5 to 12 carbon atoms, piperazinecarbonyl group,iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms,piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups having 6to 9 carbon atoms, piperidylalkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms,piperidylidenealkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylidenealkyl groups having 8 to 12 carbon atoms,guanidino groups, dialkylguanidino groups having 3 to 5 carbon atoms,phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atomsand monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms,

Y represents a group of formulae (10) to (16), and n in formulae (10)and (11) represents an integer of 1 or 2,

Z₁ represents a group of formulae (17) and (18) wherein m represents aninteger of 1 to 3, and R² represents hydroxyl group, an alkoxyl grouphaving 1 to 5 carbon atoms, amino group or a mono- or dialkylamino grouphaving 1 to 6 carbon atoms, and pharmaceutically acceptable saltsthereof.

Preferably, L represents an organic group of formula (2), W representshydrogen atom and X represents hydrogen atom, carboxymethyl group orethoxycarbonylmethyl group.

Preferably, Y represents an organic group of formula (10) and nrepresents an integer of 1.

Preferably, V₁ represents 1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)-piperizine-4-carbonyl group.

Preferably, Z₁ represents carboxyethyl group, ethoxycarbonylethyl group,carboxyvinyl group, ethoxycarbonylvinyl group, carbamoylethyl group orcarbamoylvinyl group.

Preferably, L represents an organic group of formula (2), Y representsan organic group of formula (10), V₁ represents1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)-piperizine-4-carbonyl group, and Z₁ representscarboxyethyl group, ethoxycarbonylethyl group or carbamoylethyl group.

Benzamidine derivatives of general formula (1-2) and pharmaceuticallyacceptable salts thereof have an effect of inhibiting the activatedblood coagulation factor X. In general formula (1-2), Z₁₁ is as definedabove, and E represents an oil-soluble organic group which, togetherwith other groups in general formula (1-2), imparts an effect ofinhibiting the activated blood coagulation factor X to the compounds ofgeneral formula (1-2). The effect on the activated blood coagulationfactor X can be determined by a method described in Examples in thisspecification. Groups E are those having a bonding group capable ofbonding to the benzene ring, a terminal aromatic group and/or aheterocyclic group. They are organic groups which are, as a whole,soluble in an oil. The bonding groups herein include aliphatic organicgroups, which may contain an oxygen atom or nitrogen atom, such asalkylene groups and hydroxyalkylene groups. The terminal aromatic groupsand/or heterocyclic groups include phenyl group, naphthyl group,piperidine group, pyridine group, etc. The oil-soluble organic groupsare preferably the same as —Y—L—V₁ in above formula (1-1) wherein Lrepresents an organic group of formula (2), Y represents an organicgroup of formula (10) and V₁ represents1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)-piperidine-4-carbonyl group.

Preferred groups L and more preferred groups L in general formula (1-3)are the same as those described above with reference to general formula(1-1). When L is an organic group of above formulae (2) to (5), V₂ andsubstituents thereof are as described above. Particularly preferred V₂is benzoyl group having a substituent which is selected from amongtrialkylamidino groups having 4 to 7 carbon atoms, dialkoxybenzoylgroups having 9 to 13 carbon atoms and 1-alkylpyridinio groups having 6to 9 carbon atoms.

V₂ is preferably 4-(3,4-dimethoxybenzoyl)benzoyl group,1-(1-methylpyridinium-4-yl)piperizine-4-carbonyl group or4-(1-methyl-2-imidazoline-2-yl)benzoyl group.

Y is any of above formulae (10) to (16) in general formula (1-1), and Z₂is hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenogroup or a group of formula (13-2). Preferred groups Y are the same asthose in general formula (1-1). A preferred group Z₂ is that of formula(13-2) wherein R₂₂ is carboxyl group.

Preferably L in general formula (1-3) represents an organic group offormula (2), W represents hydrogen atom, X represents hydrogen atom, V₂represents 4-(3,4-dimethoxybenzoyl)benzoyl group,1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl group or4-(1-methyl-2-imidazoline-2-yl)benzoyl group and Z₂ represents hydrogenatom or 2-carboxy-2-oxoethyl group.

Preferably L in general formula (1-3) represents an organic group offormula (2), W represents hydrogen atom, X represents hydrogen atom, V₂represents. 4-(1-methyl-2-imidazoline-2-yl)benzoyl group and Z₂represents 2-carboxy-2-oxoethyl group.

Preferred groups W, X and V₁ and more preferred groups W, X and V₁ ingeneral formula (1-4) are the same as those described above withreference to general formula (1-1). L₂ is preferably that represented byformula (2) or (4). More preferably, L₂is that represented by formula(2).

Y₂ is preferably that represented by formula (10), and R³ is preferablyhydrogen atom, an alkyl group having 1 to 3 carbon atoms or acetylgroup. R³ is more preferably hydrogen atom.

In general formula (1-4), preferably, L₂ represents an organic group offormula (2), W represents hydrogen atom and X represents any of hydrogenatom, carboxymethyl group and ethoxycarbonylmethyl group.

In general formula (1-4), preferably Y₂ represents an organic group offormula (10), and n represents an integer of 1 or 2. Particularlypreferably, n represents an integer of 1.

In general formula (1-4), V₁ is preferably1-acetimidoyl-4-piperidyloxybenzoyl group,1-(4-pyridyl)-piperidine-4-carbonyl group,1-(2,3,5,6-tetrafluoropyridine-4-yl)-piperidine-4-carbonyl group,1-(3,5-dichloropyridine-4-yl)-piperidine-4-carbonyl group,1-(6-chloropyridazine-3-yl)-piperidine-4-carbonyl group,1-(pyridazine-3-yl)-piperidine-4-carbonyl group,1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group,1-(pyrimidine-4-yl)-piperizine-4-carbonyl group,1-(4-pyridine-4-ylmethyl)-piperidine-4-carbonyl group,1-(4-pyridine-4-carbonyl)-piperidine-4-carbonyl group or4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl group.

In general formula (1-4), preferably L₂ represents an organic group, Yrepresents an organic group of formula (10), V₁ represents1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)piperizine-4-carbonyl group and R³ represents hydrogenatom.

Typical processes for producing compounds of the present invention areas follows:

A compound (27) can be obtained by reacting an aminoalkyl halide (25),in which nitrogen is protected with benzyloxycarbonyl group,t-butoxycarbonyl group base, with 3-hydroxy-4-iodobenzonitrile (26) inthe presence of a base such as potassium carbonate in a solvent such asdimethylformamide. An acrylic acid derivative (28) can be derived fromthe obtained compound (27) by, for example, condensing it with ethylacrylate or the like by, for example, Heck reaction in dimethylformamideor the like as the solvent. The protecting group on the nitrogen of theobtained compound (28) can be removed in, for example, an acidicsolution such as 4 N solution of hydrogen chloride in dioxane to obtaina corresponding amine (29).

Prot in the above formulae represents a protecting group such as Bocgroup or Z group, and Hal represents a halogen atom.

Then, the amine (29) is reacted with a condensing agent in the presenceof a base such as triethylamine in a solvent such as dimethylformamide.The amine is thus condensed with a carboxylic acid to obtain an amide(30).

Cyano group in the amide (30) obtained as described above can beconverted into amidino group by reacting amide (30) with an alcohol suchas ethanol containing a hydrogen halide such as hydrogen chloride andthen reacting the reaction product with an ammonium salt such asammonium carbonate. By these reaction steps, benzamidine derivative (31)of general formula (1-1) wherein L is represented by formula (2), Y isrepresented by formula (10) and Z is represented by formula (18) can beproduced.

Benzamidine derivative (32) of general formula (1-1) wherein L isrepresented by formula (2), Y is represented by formula (10) and Z isrepresented by formula (17) can be produced by reacting benzamidinederivative (31) in the presence of a catalyst such as palladium/carbonin an alcohol such as methanol as the solvent in hydrogen atmosphere andthen hydrolyzing the reaction product in an acidic aqueous solution suchas concentrated hydrochloric acid.

The compounds produced as described above and salts thereof can beisolated by the purification by a well-known method such as extraction,concentration, concentration under reduced pressure, extraction with asolvent, crystallization, recrystallization, redissolution or variouschromatographic techniques.

The salts of the benzamidine derivatives of the present invention arepharmaceutically acceptable ones such as salts of them with mineralacids, e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid and phosphoric acid; and organic acids, e. g. formic acid, aceticacid, trifluoroacetic aid, lactic acid, salicylic acid, mandelic acid,citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid,tannic acid, malic acid, toluenesulfonic acid, methanesulfonic acid andbenzenesulfonic acid.

The compounds and salts thereof of the present invention areadministered as they are or in the form of various medicinalcompositions to patients. The dosage forms of the medicinal compositionsare, for example, tablets, powders, pills, granules, capsules,suppositories, solutions, sugar-coated tablets and depots. They can beprepared with ordinary preparation assistants by an ordinary method. Forexample, the tablets are prepared by mixing the benzamidine derivative,the active ingredient of the present invention, with any of knownadjuvants such as inert diluents, e. g. lactose, calcium carbonate andcalcium phosphate, binders, e. g. acacia, corn starch and gelatin,extending agents, e. g. alginic acid, corn starch and pre-gelatinizedstarch, sweetening agents, e. g. sucrose, lactose and saccharin,corrigents, e. g. peppermint and cherry, and lubricants, e. g. magnesiumstearate, talc and carboxymethyl cellulose.

When the benzamidine derivatives and salts thereof of the presentinvention are used as the anticoagulants, they can be administeredeither orally or parenterally. The dose which varies depending on theage, body weight and conditions of the patient and the administrationmethod is usually 0.01 to 1,000 mg, preferably 0.1 to 50 mg, a day foradults in the oral administration, and 1 μg to 100 mg, preferably 0.01to 10 mg, in the parenteral administration.

The following Examples will further illustrate the present invention,which are only preferred embodiments of the invention and which by nomeans limit the invention.

EXAMPLE 1 Synthesis of ethyl3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylatebistrifluoroacetate

Step 1: Synthesis of ethyl 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoate

1.7 g (10.2 mmol) of ethyl 4-hydroxybenzoate, 1.76 g (9.3 mmol) of1-t-butoxycarbonyl-4-hydroxypiperidine, obtained byt-butoxycarbonylating 4-hydroxypiperidine with di-t-butyl dicarbonate inan ordinary manner, and 2.44 g (9.3 mmol) of triphenylphosphine weredissolved in 40 ml of tetrahydrofuran. 1.62 g (9.3 mmol) of diethylazodicarboxylate was added to the obtained solution at room temperature,and they were stirred overnight. After the treatment with ethyl acetateas the extraction solvent in an ordinary manner, the crude product wasobtained. It was purified by the silica gel column chromatography toobtain the title compound.

Yield: 1.57 g (4.5 mmol) (44%)

H-NMR (CDCl3) d δ 1.38 (3H, t), 1.50 (9H, s) 1.70-1.80 (2H, m),1.90-2.00 (2H, m), 3.30-3.41 (2H, m), 3.63-3.75 (2H, m), 4.35 (2H, q),4.55 (1H, m), 6.90 (2H, d), 8.00 (2H, d)

Step 2: Synthesis of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid

847 mg (2.43 mmol) of ethyl4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoate was dissolved in 50 ml ofethanol. 5 ml of 1 N sodium hydroxide solution was added to the obtainedsolution, and they were stirred at room temperature for 3 days. Thereaction solution was concentrated and then treated with ethyl acetateas the extraction solvent in an ordinary manner to obtain the titlecompound.

Yield: 697 mg (2.2 mmol) (92%)

H-NMR (CDCl3) d δ 1.50 (9H, s), 1.70-2.00 (4H, m), 3.30-3.40 (2H, m),3.65-3.75 (2H, m), 4.60 (1H, s), 6.95 (2H, d), 8.05 (2H, d)

Step 3: Synthesis of 3-hydroxy-4-iodobenzoic acid

30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml ofacetic acid. 53.0 g (326 mmol) of iodine monochloride was added to theobtained solution at room temperature. After stirring at 45° C. for 15hours, the solvent was evaporated under reduced pressure. The residuethus obtained was washed with 500 ml of 1% aqueous sodium thiosulfatesolution twice and with 500 ml of water twice and then dried to solid at80° C. under reduced pressure to obtain the title compound.

Yield: 17.2 g (65.2 mmol) (30%)

MS (FAB, m/z) 265 (MH+)

H-NMR (DMSO-d6) δ 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)

Step 4: Synthesis of 3-hydroxy-4-iodobenzonitrile

22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid was dissolved in 300ml of tetrahydrofuran. 19.7 ml (206 mmol) of ethyl chloroformate and28.7 ml (206 mmol) of triethylamine were added to the obtained solutionat 0° C. After stirring for 15 minutes, triethylamine hydrochloride thusformed was separated by the filtration. The filtrate was added to 300 mlof tetrahydrofuran solution, obtained by bubbling ammonia, at 0° C.After stirring at room temperature for 10 hours, the solvent wasevaporated under reduced pressure. The obtained residue was dissolved in450 ml of dioxane. 17.4 ml (117 mmol) of anhydrous trifluoroaceticanhydride and 21.8 ml (269 mmol) of pyridine were added to the obtainedsolution at 0° C. After stirring at room temperature for 18 hours, thesolvent was evaporated under reduced pressure, and the residue wastreated with chloroform as the extraction solvent in an ordinary mannerto obtain an oily residue. The residue was dissolved in 180 ml oftetrahydrofuran/methanol (1:1). 90 ml (90.0 mmol) of 1 N aqueous sodiumhydroxide solution was added to the obtained solution at roomtemperature. After stirring them for 4 hours, the solvent was evaporatedunder reduced pressure. The obtained residue was washed withdichloromethane. After acidifying with 1 N hydrogen chloride, theproduct was treated with ethyl acetate as the extraction solvent in anordinary manner to obtain the crude product, which was then purified bythe silica gel column chromatography to obtain the title compound.

Yield: 9.29 g (37.9 mmol) (42%)

MS (FAB, m/z) 246 (MH+)

H-NMR (CDCl3) δ 5.63 (1H, br), 6.96 (1H, dd), 7.23 (1H, d), 7.79 (1H, d)

Step 5 Synthesis of t-butyl (2-bromoethyl)carbamate

9.22 g (45 mmol) of 2-bromoethylamine hydrobromide was dissolved in 100ml of dichloromethane. 7.64 ml (35 mmol) of di-t-butyl dicarbonate, 10.0g (99 mmol) of triethylamine and 100 mg (0.82 mmol) of4-(dimethylamino)pyridine were added to the obtained solution, and theywere stirred overnight. The obtained mixture was treated withdichloromethane as the extraction solvent in an ordinary manner toobtain the title compound.

Yield: 5.99 g (26.7 mmol) (76%)

H-NMR (CDCl3) δ 1.45 (9H, s), 3.46 (2H, dt), 3.51 (2H, t), 4.95 (1H, br)

Step 6: Synthesis of3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile

18.5 g (82.6 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in200 ml of DMF. 10.1 g (41.3 mmol) of 3-hydroxy-4-iodobenzonitrile and5.7 g (41.3 mmol) of potassium carbonate were added to the obtainedsolution, and they were stirred at 75° C. for 3 hours. After thetreatment with ethyl acetate as the extraction solvent in an ordinarymanner, the title compound was obtained.

Yield: 11.0 g (28.4 mmol) (69%).

H-NMR (CDCl3) δ 1.46 (9H, s), 3.62 (2H, dt), 4.12 (2H, t), 7.02 (2H, d),7.88 (2H, d).

Step 7: Synthesis of ethyl3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylate

11.0 g (28.4 mmol) of3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile was dissolved in200 ml of DMF. 15.4 ml (142 mmol) of ethyl acrylate, 20 ml (142 mmol) oftriethylamine and 127 mg (0.567 mmol) of palladium acetate were added tothe obtained solution. They were stirred at 100° C. overnight and thentreated with ethyl acetate as the extraction solvent in an ordinarymanner to obtain the crude product. After the purification by the silicagel column chromatography, the title compound was obtained.

Yield: 9.6 g (26.7 mmol) (94%)

H-NMR (CDCl3) δ 1.38 (3H, t), 1.46 (9H, s), 3.62 (2H, dt), 4.16 (2H, t),4.28 (2H, q), 6.56 (1H, d), 7.16 (1H, d), 7.27 (1H, d), 7.60 (1H, d),7.96 (1H, d)

Step 8: Synthesis of ethyl3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylate

2.72 g (7.56 mmol) of ethyl3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylate wasdissolved in a mixture of 10 ml of dioxane and 20 ml of 4 N solution ofhydrogen chloride in dioxane, and the obtained solution was stirred atroom temperature for 4 hours.

The solvent was evaporated under reduced pressure, and the obtainedcrude product was dissolved in 50 ml of dichloromethane. 2.67 g (8.32mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 1.59 g (8.32mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,1.12 g (8.32 mmol) of 1-hydroxybenzotriazole and 3.16 ml (22.7 mmol) oftriethylamine were added to the obtained solution, and they were stirredat room temperature overnight. After the treatment with dichloromethaneas the extraction solvent in an ordinary manner, the obtained crudeproduct was purified by the silica gel column chromatography to obtainthe title compound.

Yield: 3.0 g (5.33 mmol) (71%)

H-NMR (CDCl3) δ 1.33 (3H, t), 1.47 (9H, s), 1.64-1.79 (2H, m), 1.86-1.98(2H, m), 3.24-3.42 (2H, m), 3.60-3.73 (2H, m), 3.92 (2H, dt), 4.24 (2H,q), 4.28 (2H, t), 4.45-4.53 (1H, m), 6.57 (1H, d), 6.77 (1H, t), 6.88(2H, d), 7.18 (1H, d), 7.23 (1H, d), 7.58 (1H, d), 7.77 (2H, d), 7.97(1H, d)

Step 9: Synthesis of ethyl3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylatebistrifluoroacetate

3.0 g (5.33 mmol) of ethyl3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylatewas dissolved in a mixture of 4 ml of ethanol and 20 ml of 4 N solutionof hydrogen chloride in dioxane, and the obtained solution was stirredat room temperature for 3 days. The solvent was evaporated, and theobtained residue was dissolved in 20 ml of ethanol. 906 mg of ammoniumcarbonate was added to the obtained solution, and they were stirred atroom temperature overnight. The solvent was evaporated, and the obtainedresidue was dissolved in 20 ml of ethanol. 3.28 g (26.7 mmol) of ethylacetimidate and 7.42 ml (53.3 mmol) of triethylamine were added to thesolution, and they were stirred at room temperature overnight. Thesolvent was evaporated, and the obtained crude product was subjected toreversed phase high-performance liquid chromatography with silica gelchemically bonded with octadodecyl group as the filler. After theelution with a mixed solution of water and acetonitrile containing 0.1%(v/v) of trifluoroacetic acid, the intended fraction was freeze-dried toobtain the title compound.

Yield: 2.3 g (3.07 mmol) (37%)

MS (ESI, m/z) 522 (MH+)

H-NMR (DMSO-d6) δ 1.23 (3H, t), 1.67-1.87 (2H, m), 2.00-2.25 (2H, m),2.29 (3H, s), 3.45-3.60 (2H, m), 3.66-3.77 (4H, m), 4.17 (2H, q), 4.34(2H, t), 4.73-4.76 (1H, m), 6.79 (1H, d), 7.05 (2H, t), 7.43 (1H, d),7.56 (1H, d), 7.84 (2H, d), 7.92 (1H, br), 7.97 (1H, d), 8.64 (2H, br),9.19 (1H, br), 9.37 (4H, br)

EXAMPLE 2 Synthesis of3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylicacid bistrifluoroacetate

550 mg (0.734 mmol) of ethyl3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylatebistrifluoroacetate was dissolved in 10 ml of concentrated hydrochloricacid, and the obtained solution was stirred at 50° C. for 6 hours. Thesolvent was evaporated and the obtained crude product was treated in thesame manner as that in step 9 in Example 1 to obtain the title compound.

Yield: 440 mg (0.610 mol) (83%)

MS (ESI, m/z) 494 (MH+)

H-NMR (DMSO-d6) δ 1.67-1.87 (2H, m), 2.00-2.17 (2H, m), 2.29 (3H, s),3.45-3.59 (2H, m), 3.64-3.76 (4H, m), 4.33 (2H, t), 4.73-4.87 (1H, m),6.70 (1H, d), 7.06 (2H, d), 7.43 (1H, d), 7.54 (1H, br), 7.85 (2H, d),7.90 (1H, br), 7.95 (1H, d), 8.62 (1H, br), 8.70 (1H, t), 9.17 (1H, br),9.28 (2H, br), 9.36 (2H, br)

EXAMPLE 3 Synthesis of ethyl3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]propionatebistrifluoroacetate

1.2 g (1.60 mmol) of ethyl3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylatebistrifluoroacetate was dissolved in 50 ml of methanol. 100 mg ofpalladium/carbon was added to the obtained solution, and they werestirred in the presence of hydrogen overnight. The solvent wasevaporated and the obtained crude product was treated in the same manneras that in step 9 in Example 1 to obtain the title compound.

Yield: 1.1 g (1.46 mmol) (91%)

MS (ESI, m/z) 524 (MH+)

H-NMR (DMSO-d6) δ 1.16 (3H, t), 1.67-1.76 (2H, m), 2.00-2.25 (2H, m),2.29 (3H, s), 2.58 (2H, t), 2.90 (2H, t), 3.46-3.58 (2H, m), 3.63-3.84(4H, m) 3.98 (2H, q), 4.23 (2H, t), 4.74-4.87 (1H, m), 7.08 (1H, d),7.36 (1H, br), 7.38 (2H, d), 7.84 (2H, d), 8.61 (2H, br), 9.11 (2H, br),9.16 (1H, br), 9.24 (2H, br)

EXAMPLE 4 Synthesis of3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]propionicacid bistrifluoroacetate

600 mg (0.799 mmol) of ethyl3-[4-amidino-2-(2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]propionatebistrifluoroacetate was dissolved in 10 ml of concentrated hydrochloricacid, and the obtained solution was stirred at 50° C. for 4 hours. Thesolvent was evaporated and the obtained crude product was treated in thesame manner as that in step 9 in Example 1 to obtain the title compound.

Yield: 480 mg (0.663 mol) (77%)

MS (ESI, m/z) 496 (MH+)

H-NMR (DMSO-d6) δ 166-1.87 (2H, m), 2.02-2.17 (2H, m), 2.29 (3H, s),2.52 (2H, t), 2.78 (2H, t), 3.44-3.62 (2H, m), 3.64-3.75 (4H, m), 4.42(2H, t), 4.74-4.86 (1H, m), 7.06 (2H, d), 7.37 (1H, br), 7.39 (2H, d),7.85 (2H, d). 8.64 (2H, br), 9.19 (1H, d), 9.23 (2H, br), 9.25 (2H, br)

EXAMPLE 5 Synthesis of ethyl3-[4-amidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionatebistrifluoroacetate

Step 1 Synthesis of ethyl 1-(4-pyridyl)-4-piperidinecarboxylate

4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g (26.6 mmol)of ethyl piperidine-4-carboxylate and 7.4 ml (53.2 mmol) oftriethylamine were stirred in 100 ml of xylene at 130° C. for 24 hours.After the treatment with dichloromethane as the extraction solvent in anordinary manner, the obtained crude product was purified by the silicagel column chromatography to obtain the title compound.

Yield: 2.95 g (12.6 mmol) (47%)

H-NMR (CDCl3) δ 1.25 (3H, t), 1.71-1.85 (2H, m), 2.00 (2H, d), 2.50-2.60(1H, m), 2.90 (2H, t), 3.81 (2H, d), 4.20 (2H, q), 6.66 (2H, d), 8.26(2H, d)

Step 2: Synthesis of 1-(4-pyridyl)-4-piperidinecarboxylic acidhydrochloride

2.95 g (12.6 mmol) of ethyl 1-(4-pyridyl)-4-piperidinecarboxylate wasstirred in 100 ml of dioxane. 50 ml of 1 N hydrochloric acid was addedto the obtained mixture, and they were stirred at 95° C. for 20 hours.The solvent was evaporated to obtain the crude title compound.

Yield: 3.21 g (11.5 mmol) (91%)

H-NMR (DMSO-d6) δ 1.54 (2H, t), 1.90 (2H, t), 2.60-2.70 (1H, m), 3.30(2H, t), 4.10 (2H, d), 7.19 (2H, d), 8.20 (2H, d)

Step 3: Synthesis of ethyl3-[4-cyano-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]acrylate

3.0 g (8.33 mmol) of ethyl3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylate wasdissolved in a mixture of 20 ml of 4 N solution of hydrogen chloride indioxane and 10 ml of dioxane. The obtained solution was stirred at roomtemperature for 4 hours. The solvent was evaporated and the residue wasdissolved in 50 ml of DMF. 2.22 g (9.17 mmol) of1-(4-pyridyl)-4-piperidinecarboxyic acid hydrochloride, 4.27 g (9.17mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 3.48 ml(25.0 mmol) of triethylamine were added to the obtained solution, andthey were stirred at room temperature for 3 days. The solvent wasevaporated, and the obtained crude product was purified by the silicagel column chromatography to obtain the title compound.

Yield: 2.3 g (5.13 mmol) (62%)

H-NMR (DMSO-d6) δ 1.26 (3H, t); 1.50-1.68 (2H, m), 1.68-1.73 (2H, m),2.62-2.68 (1H, m), 2.94-3.06 (2H, m), 3.40-3.53 (2H, m), 3.95-4.25 (6H,m),6.76 (1H, dd), 6.94 (2H, d), 7.44 (1H, dd), 7.62 (1H, br), 7.83 (1H,dd), 7.90 (1H, d), 9.01 (1H, t), 8.15 (2H, d)

Step 4: Synthesis of ethyl3-[4-amidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionatebistrifluoroacetate

2.3 g (5.13 mmol) of ethyl3-[4-cyano-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]acrylatewas dissolved in a mixture of 20 ml of 4 N solution of hydrogen chloridein dioxane and 4 ml of ethanol. The obtained solution was stirred atroom temperature for 4 days. The solvent was evaporated and the residuewas dissolved in 30 ml of ethanol. 872 mg of ammonium carbonate wasadded to the obtained solution, and they were stirred at roomtemperature overnight. The solvent was evaporated, and the residue wasdissolved in 30 ml of methanol. 200 mg of palladium/carbon was added tothe resultant solution, and they were stirred in the presence ofhydrogen overnight. The solvent was evaporated, and the obtained crudeproduct was treated in the same manner as that in step 9 in Example 1 toobtain the title compound.

Yield: 1.5 g (2.16 mmol) (42%)

MS (ESI, m/z) 468 (MH+)

H-NMR (DMSO-d6) δ 1.15 (3H, t), 1.50-1.67 (2H, m), 1.76-1.81 (2H, m),2.52-2.60 (1H, m), 2.62 (2H, dd), 2.89 (2H, dd), 3.15-3.28 (2H, m), 3.49(2H, dt), 4.03 (2H, q), 4.12 (2H, t), 4.20 (2H, d), 7.19 (2H, d), 7.37(3H, br), 8.18 (1H, d), 8.21 (2H, d), 9.23 (2H, br), 9.25 (2H, br)

EXAMPLE 6 Synthesis of3-[4-amidino-2-(2-((1-pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

250 mg (0.359 mmol) of ethyl3-[4-amidino-2-(2-((1-pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy]phenyl]propionatebistrifluoroacetate was dissolved in 10 ml of concentrated hydrochloricacid, and the obtained solution was stirred at 50° C. for 4 hours. Thesolvent was evaporated and the obtained crude product was treated in thesame manner as that in step 9 in Example 1 to obtain the title compound.

Yield: 480 mg (0.330 mol) (92%)

MS (ESI, m/z) 440 (MH+)

H-NMR (DMSO-d6) δ 1.50-1.67 (2H, m), 1.76-1.92 (2H, m), 2.54 (2H, dd),2.55-2.67 (1H, m), 2.88 (2H, dd), 3.12-3.29 (2H, m), 3.49 (2H, dt), 4.12(2H, t), 4.20 (2H, d), 7.18 (2H, d), 7.36 (2H, br), 7.37 (1H, d), 8.18(1H, d), 8.20 (2H, d), 9.14 (2H, br), 9.24 (2H, br)

EXAMPLE 7 Synthesis of ethyl(3R)-3-[4-amidino-2-(3-ethoxycarbonyl-2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)propoxy]phenyl]acrylatebistrifluoroacetate

Step 1: Synthesis of benzyl(3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate

15.0 g (46.4 mmol) of β-benzyl N-t-butoxycarbonyl-D-aspartate and 6.47ml (46.4 mmol) of triethylamine were dissolved in 230 ml oftetrahydrofuran. 4.4 ml (46.4 mmol) of ethyl chloroformate was added tothe obtained solution under cooling with ice, and they were stirred for15 minutes. Precipitates thus formed were removed by the filtrationunder suction. 5 g of ice and 1.8 g (46.6 mmol) of sodium borohydridewere added to the filtrate under cooling with ice, and they were stirredfor 1.5 hours. Then 200 ml of 1 N aqueous hydrogen chloride solution wasadded to the reaction mixture, and they were further stirred at roomtemperature for one hour. After the treatment with ethyl acetate as theextraction solvent in an ordinary manner, the obtained crude product waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 10.2 g (32.8 mmol) (71%)

H-NMR (CDCl3) d 1.42 (9H, s), 2.66 (2H, d), 3.65 (2H, dd), 4.00 (1H,ddt), 5.14 (2H, s), 7.35-7.40 (5H, m)

Step 2: Synthesis of benzyl(3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-iodophenoxy)butanoate

10.16 g (32.8 mmol) of benzyl(3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 mlof toluene. 10.5 g (42.7 mmol) of 3-hydroxy-4-iodobenzonitrile, 11.2 g(42.7 mmol) of triphenylphosphine and 7.4 g (42.7 mmol) ofN,N,N′,N′-tetramethylazodicarboxamide were added to the obtainedsolution under cooling with ice, and they were stirred at roomtemperature overnight.

The solvent was evaporated, and the residue was purified by the silicagel column chromatography to obtain the title compound.

Yield: 11.9 g (22.1 mmol) (67%)

H-NMR (CDCl3) d 1.47 (9H, s), 2.90 (2H, t), 4.03 (1H, dd), 4.15 (1H,dd),4.40-4.50 (1H, m), 5.19 (2H, s), 7.01 (1H, d), 7.30 (1H, s),7.35-7.40 (5H, m), 7.92 (1H, d)

Step 3: Synthesis of ethyl(3R)-3-[2-(3-benzyloxycarbonyl-2-t-butoxycarbonylamino-propoxy)-4-cyanophenyl]acrylate

20.0 g (37.3 mmol) of benzyl(3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-iodophenoxy)butanoate wasdissolved in 150 ml of DMF. 10.1 ml (93.3 mmol) of ethyl acrylate, 13 ml(93.3 mmol) of triethylamine and 167 mg (0.567 mmol) of palladiumacetate were added to the obtained solution, and they were stirred at100° C. overnight. After the treatment with ethyl acetate as theextraction solvent in an ordinary manner, the obtained crude product waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 13 g (25.6 mmol) (69%)

H-NMR (CDCl3) δ 1.36 (3H, t), 1.44 (9H, s), 2.77-2.84 (2H, m),4.03-4.22(2H, m), 4.24 (2H, q), 4.37-4.50 (1H, m), 5.16 (2H, s), 6.50(1H, d), 7.19 (1H, d), 7.23-7.36 (6H, m), 7.61 (1H, d), 7.93 (1H, d)

Step 4: Synthesis of ethyl(3R)-3-[2-(2-amino-3-benzyloxycarbonyl-propoxy)-4-cyanophenyl]acrylatemonohydrochloride

13 g (25.6 mmol) of ethyl(3R)-3-[2-(3-benzyloxycarbonyl-2-t-butoxycarbonylamino-propoxy)-4-cyanophenyl]acrylatewas dissolved in a mixture of 20 ml of dioxane and 20 ml of 4 N solutionof hydrogen chloride in dioxane, and the obtained solution was stirredat room temperature overnight. The solvent was evaporated under reducedpressure to obtain the crude product.

Yield: 7.8 g (17.6 mmol) (69%)

Step 5: Synthesis of ethyl(3R)-3-[2-(3-benzyloxycarbonyl-2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)propoxy)-4-cyanophenyl]acrylate

3.5 g (7.87 mmol) of ethyl(3R)-3-[2-(2-amino-3-benzyloxycarbonyl-propoxy)-4-cyanophenyl]acrylatemonohydrochloride was dissolved in 50 ml of DMF. 2.8 g (8.65 mmol) of4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 1.65 g (8.65 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.17 g(8.65 mmol) of 1-hydroxybenzotriazole and 3.28 ml (23.6 mmol) oftriethylamine were added to the obtained solution, and they were stirredat room temperature overnight. After the treatment with ethyl acetate asthe extraction solvent in an ordinary manner, the obtained crude productwas purified by the silica gel column chromatography to obtain the titlecompound.

Yield: 3.2 g (4.50 mmol) (57%)

H-NMR (CDCl3) δ 1.32 (3H, t), 1.47 (9H, s), 1.66-1.83 (3H, m), 1.88-2.02(2H, m), 2.83-3.07 (2H, m), 3.30-3.42 (2H, m), 3.63-3.78 (2H, m),4.04-4.25 (2H, m), 4.27 (2H, q), 4.50-4.60 (2H, m), 4.84-4.97 (1H, m),5.30 (2H, s), 6.52 (1H, d), 6.91 (1H, d), 7.11 (1H, br), 7.29 (7H, br),7.57 (1H, d), 7.73 (2H, d), 7.92 (1H, d)

Step 6: Synthesis of ethyl(3R)-3-[4-amidino-2-(3-ethoxycarbonyl-2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)propoxy)phenyl]acrylatebistrifluoroacetate

3.2 g (4.50 mmol) of ethyl(3R)-3-[2-(3-benzyloxycarbonyl-2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)propoxy)-4-cyanophenyl]acrylatewas dissolved in a mixture of 25 ml of 4 N solution of hydrogen chloridein dioxane and 5 ml of ethanol. The obtained solution was stirred atroom temperature for 4 days. The solvent was evaporated, and the residuewas dissolved in 20 ml of ethanol. 760 mg of ammonium carbonate wasadded to the obtained solution, and they were stirred at roomtemperature overnight. The solvent was evaporated, and the obtainedresidue was dissolved in 50 ml of ethanol. 3.0 g (26.7 mmol) of ethylacetimidate and 5 ml (35.6 mmol) of triethylamine were added to theobtained solution, and they were stirred at room temperature overnight.The solvent was evaporated, and the obtained crude product was treatedin the same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 550 mg (0.659 mmol) (17%)

MS (ESI, m/z) 608 (MH+)

H-NMR (DMSO-d6) δ 1.14 (3H, t), 1.22 (3H, t), 1.68-1.76 (2H, m),2.00-2.16 (2H, m), 2.29 (3H, s), 2.80 (2H, d), 3.47-3.60 (2H, m),3.70-3.85 (2H, m), 4.05 (2H, q), 4.14 (2H, q), 4.23-4.35 (2H, m),4.70-4.88 (2H, m), 6.77 (1H, d), 7.06 (2H, d), 7.43 (1H, d), 7.56 (1H,br), 7.82 (2H, d), 7.87 (1H, d), 7.97 (1H, d), 8.50 (1H, d), 8.60 (1H,br), 9.15 (1H, br), 9.23 (2H, br), 9.35 (2H, br)

EXAMPLE 8 Synthesis of(3R)-3-[4-amidino-2-(3-ethoxycarbonyl-2-(4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino)propoxy)phenyl]acrylicacid bistrifluoroacetate

200 mg (0.240 mmol) of ethyl(3R)-3-[4-amidino-2-(3-ethoxycarbonyl-2-(4-(1-(l1-acetimidoyl)-4-piperidyloxy)benzoylamino)propoxy)phenyl]acrylatebistrifluoroacetate was dissolved in 5 ml of concentrated hydrochloricacid, and the obtained solution was stirred at 50° C. for 2 hours. Thesolvent was evaporated, and the obtained crude product was treated inthe same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 120 mg (0.154 mmol) (64%)

MS (ESI, m/z) 552 (MH+)

H-NMR (DMSO-d6) δ 1.70-1.85 (2H, m), 2.00-2.14 (2H, m), 2.29 (3H, s),2.78 (2H, d), 3.71-3.84 (2H, m), 4.22-4.34 (2H, m), 4.29 (2H, d),4.62-4.73 (1H, m), 4.77-4.86 (1H, m), 6.68 (1H, d), 7.06 (2H, d), 7.43(1H, d), 7.56 (1H, br), 7.82 (2H, d), 7.86 (1H, d), 7.94 (1H, d), 8.50(1H, d), 8.62 (1H, br), 9.17 (1H, br), 9.31 (2H, br), 9.32 (2H, br)

EXAMPLE 9 Synthesis of ethyl(3R)-4-[5-amidino-2-(2-ethoxycarbonylethyl)phenoxy]-3-[4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino]butanoatebistrifluoroacetate

3.2 g (4.50 mmol) of ethyl(3R)-3-[2-(3-benzyloxycarbonyl-2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)propoxy)-4-cyanophenyl]acrylatewas dissolved in a mixture of 25 ml of 4 N solution of hydrogen chloridein dioxane and 5 ml of ethanol. The obtained solution was stirred atroom temperature for 4 days. The solvent was evaporated, and the residuewas dissolved in 20 ml of ethanol. 765 mg of ammonium carbonate wasadded to the obtained solution, and they were stirred at roomtemperature overnight. The solvent was evaporated, and the obtainedresidue was dissolved in 50 ml of ethanol. 2.77 g (26.7 mmol) of ethylacetimidate and 5 ml (35.6 mmol) of triethylamine were added to theobtained solution, and they were stirred at room temperature overnight.The solvent was evaporated, and the obtained crude product was dissolvedin 50 ml of water containing 0.1% (v/v) of trifluoroacetic acid and thenpurified by the reversed phase medium-pressure preparativechromatography with silica gel packing material (LiChroprep RP-18 37×440mm) chemically bonded to octadodecyl group, followed by the elution witha mixed solvent of water and acetonitrile containing 0.1% (v/v) oftrifluoroacetic acid. The obtained purified product was dissolved in 50ml of methanol. 600 mg of palladium/carbon was added to the obtainedsolution, and they were stirred in the presence of hydrogen overnight.The solvent was evaporated and the obtained crude product was treated inthe same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 920 mg (1.10 mmol) (24%)

MS (ESI, m/z) 608 (MH+)

H-NMR (DMSO-d6) δ 1.13 (3H, t), 1.15 (3H, t), 1.67-1.86 (2H, m),2.00-2.16 (2H, m), 2.29 (3H, s), 2.56 (2H, dd), 2.82 (2H, dd), 2.83-2.98(2H, m), 3.47-3.62 (2H, m), 3.64-3.92 (2H, m), 3.98 (2H, q), 4.06 (2H,q), 4.18 (2H, d), 4.67-4.88 (2H, m), 7.06 (2H, d), 7.37 (1H, br), 7.38(2H, d), 7.82 (2H, d), 8.45 (1H, d), 8.62 (1H, br), 9.11 (2H, br), 9.16(1H, br), 9.23 (2H, br)

EXAMPLE 10 Synthesis of(3R)-4-[5-amidino-2-(2-carboxyethyl)phenoxy]-3-[4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino]butanoicacid bistrifluoroacetate

500 mg (0.600 mmol) of ethyl(3R)-4-[5-amidino-2-(2-ethoxycarbonylethyl)phenoxy]-3-[4-(1-(1-acetimidoyl)-4-piperidyloxy)benzoylamino]butanoatebistrifluoroacetate was dissolved in 5 ml of concentrated hydrochloricacid, and the obtained solution was stirred at 50° C. for 2 hours. Thesolvent was evaporated, and the obtained crude product was treated inthe same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 340 mg (0.435 mmol) (73%)

MS (ESI, m/z) 554 (MH+)

H-NMR (DMSO-d6) δ 1.68-1.86 (2H, m), 2.00-2.17 (2H, m), 2.29 (3H, s),2.52 (2H, d), 2.76 (2H, dd), 2.83-2.96 (2H, m), 3.48-3.52 (2H, m),3.69-3.76 (2H, m), 4.12-4.24 (2H, m), 4.63-4.73 (1H, m), 4.75-4.86 (1H,m), 7.06 (2H, d), 7.37 (1H, br), 7.39 (2H, d), 7.83 (2H, d), 8.44 (1H,d), 8.61 (1H, br), 9.09 (2H, br), 9.15 (1H, br), 9.22 (2H, br)

EXAMPLE 11 Synthesis of3-[4-amidino-2-(2-(4-(1-acetimidoyl-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylamidebistrifluoroacetate

Step 1: Synthesis of3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylamide

3.0 g (5.33 mmol) of ethyl3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylatewas dissolved in 100 ml of ethanol. 15 ml of 1 N aqueous sodiumhydroxide solution was added to the obtained solution, and they werestirred at room temperature overnight. The solvent was evaporated underreduced pressure. 1 N aqueous hydrochloric acid/ice solution was addedto the obtained crude product, and they were treated with ethyl acetateas the extraction solvent in an ordinary manner to obtain the crudeproduct. 30 ml of N,N-dimethylformamide, 0.75 g (5.55 mmol) of1-hydroxybenzotriazole (hydrous), 1.40 g (25.2 mmol) of ammoniumcarbamate, 2 ml (0.015 mmol) of triethylamine and 2.12 g (11.09 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were addedto the crude product, and they were stirred overnight. After theevaporation of the solvent followed by the treatment with ethyl acetateas the extraction solvent in an ordinary manner, the solvent wasevaporated, and the obtained crude product was purified by the silicagel column chromatography to obtain the title compound.

Yield: 1.89 g (3.54 mmol) (66%)

H-NMR (CDCl3) δ 1.45 (9H, s), 1.60-2.00 (4H, m), 3.28-3.73 (4H, m),4.02-4.23 (4H, m), 4.51 (1H, br), 5.60 (1H, br), 6.89 (2H, d), 7.00-7.68(5H, m), 7.75 (2H, d)

Step 2: Synthesis of3-[4-amidino-2-(2-(4-(1-acetamidoyl-benzoylamino)-4-piperidyloxy)ethoxy)phenyl]acrylamidebistrifluoroacetate

1.89 g (3.54 mmol) of3-[4-cyano-2-(2-(4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoylamino)ethoxy)phenyl]acrylamidewas dissolved in a mixture of 40 ml of 4 N solution of hydrogen chloridein dioxane and 4 ml of ethanol, and they were stirred at roomtemperature overnight. The solvent was evaporated under reducedpressure, and the residue was dissolved in 60 ml of ethanol. 0.97 g(17.15 mmol) of ammonium carbamate was added to the obtained solution,and they were stirred at room temperature overnight. The solvent wasevaporated, and the obtained crude product was treated in the samemanner as that in step 9 in Example 1 to obtain the purified product.1.86 g (3.37 mmol) of the purified product was dissolved in 30 ml ofethanol. 1.27 g (10.29 mmol) of ethyl acetimide hydrochloride and 2.4 ml(17.15 mmol) of triethylamine were added to the obtained solution, andthey were stirred overnight. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 1.10 g (1.53 mmol) (43%)

MS (ESI,m/z) 493 (MH+)

H-NMR (DMSO) δ 1.68-2.18 (4H, m), 2.29 (3H, s), 3.45-3.90 (6H, m), 4.30(2H, t), 4.80 (1H, br), 6.92 (1H, d), 7.10 (2H, d), 7.23 (1H, br), 7.45(1H, d), 7.52 (1H, s), 7.62 (1H, d), 7.64 (1H, br), 7.74 (1H, d), 7.85(2H, d), 8.62 (1H, br), 8.74 (1H, t), 9.16 (1H, br), 9.22-9.42 (4H, m)

EXAMPLE 12 Synthesis of3-[4-amidino-2-(2-(4-(1-acetamidoyl)-4-piperidyloxy)benzoylamino)ethoxy)phenyl]propionamidebistrifluoroacetate

1.10 g (1.53 mmol) of3-[4-amidino-2-(2-(4-(1-acetimidoyl)benzoylamino)ethoxy)phenyl]acrylamidebistrifluoroacetate was dissolved in 100 ml of ethanol. 220 mg of 10%palladium/carbon (50% hydrous) was added to the obtained solution, andthey were stirred in the presence of hydrogen overnight. The reactionsolution was filtered through Celite. The solvent was evaporated, andthe obtained crude product was treated in the same manner as that instep 9 in Example 1 to obtain the title compound.

Yield: 0.82 g (1.13 mmol) (74%)

MS (ESI,m/z) 495 (MH+)

H-NMR (DMSO) δ 1.68-2.17 (4H, m), 2.28 (3H, s), 2.35 (2H, t), 2.85 (2H,t), 3.47-3.85 (6H, m), 4.20 (2H, t), 4.80 (1H, br), 6.80 (1H, br), 7.06(2H, d), 7.30 (1H, br), 7.33-7.42 (3H, m), 7.85 (2H, d), 8.56-8.70 (2H,m), 9.07-9.28 (5H, m)

EXAMPLE 13 Synthesis of(3R)-4-[5-amidino-2-(2-carboxyethyl)phenoxy]-3-[(1-(pyridine-4-yl)piperidine-4-carbonyl)amino]butanoicacid bistrifluoroacetate

Step 1: Synthesis of ethyl(3R)-3-[2-(3-benzyloxycarbonyl-2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)propoxy)-4-cyanophenyl]acrylate

7.50 g (14.7 mmol) of ethyl(3R)-3-[2-(t-butoxycarbonylamino)-3-benzyloxycarbonyl-propoxy]-4-cyanophenyl]acrylatewas dissolved in a mixture of 14.7 ml of dioxane and 22.1 ml of 4 Nsolution of hydrogen chloride in dioxane, and the obtained solution wasstirred at room temperature for 4 hours. The solvent was evaporated.6.73 g (of 7.08 g in total) of the crude product obtained by evaporatingthe solvent was dissolved in 70 ml of DMF. 3.74 g (15.4 mmol) of1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 3.08 g (18.2mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 8.6 ml (61.6mmol) of triethylamine were added to the obtained solution at 10° C.,and they were stirred for 16 hours.

After the treatment with ethyl acetate as the extraction solvent in anordinary manner, the obtained crude product was purified by the silicagel column chromatography to obtain the title compound.

MS (HRFABH+) 597.27 (MH+)

Yield: 7.83 g (13.1 mmol) (94%)

H-NMR (DMSO) δ 1.23 (3H, t), 1.50-1.64 (2H, m), 1.69-1.83 (2H, m),2.42-2.51 (1H, m), 2.62-2.77 (2H, m), 3.03-3.41 (2H, m), 4.06-4.38 (6H,m), 4.49-4.61 (1H, m). 5.10 (2H, s), 6.74 (1H, d), 7.08 (2H, d), 7.36(5H, br), 7.45 (1H, d), 7.62 (1H, br), 7.83 (1H, d), 7.92 (1H, d), 8.18(3H,brd),

Step 2: Synthesis of(3R)-4-[5-amidino-2-(2-carboxyethyl)phenoxy]-3-[(1-(pyridine-4-yl)piperidine-4-carbonyl)amino]butanoicacid bistrifluoroacetate

5.37 g (9.0 mmol) of ethyl(3R)-3-[2-(3-benzyloxycarbonyl-2-((1-pyridine-4-yl)piperidine-4-carbonyl)amino)propoxy]-4-cyanophenyl]acrylatewas dissolved in a mixture of 45 ml of 4 N solution of hydrogen chloridein dioxane and 9 ml of ethanol, and the obtained solution was stirred atroom temperature overnight. The solvent was evaporated under reducedpressure, and the residue was dissolved in 36 ml of ethanol. 1.56 g(16.2 mmol) of ammonium carbonate was added to the obtained solution,and they were stirred at room temperature overnight. The solvent wasevaporated. 5.48 g (of 6.09 g in total) of the crude product obtained bythe evaporation of the solvent was dissolved in 54 ml of methanol. 548mg of 10% palladium/carbon was added to the obtained solution, and theywere stirred in the presence of hydrogen overnight. The reactionsolution was filtered through Celite. The solvent was evaporated, and3.11 g (of 4.44 g in total) of the crude product obtained by theevaporation of the solvent was dissolved in 28 ml of 6 N aqueoushydrochloric acid solution. After stirring the obtained solution at 60°C. for 2 hours, the solvent was evaporated. 60% of the crude productobtained by the evaporation of the solvent was treated in the samemanner as that in step 9 in Example 1 to obtain the title compound.

MS (ESI, m/z) 498 (MH+)

MS (HRFABH+) 498.24(MH+)

Yield: 1.34 g (1.85 mmol) (33%)

H-NMR (DMSO) δ 1.52-1.64 (2H, m), 1.78-1.88 (2H, m), 2.50-2.639 (5H, m),2.81-2.96 (2H, m), 3.17-3.24 (2H, m), 4.07-4.23 (4H, m), 4.40-4.51 (1H,m). 7.19 (2H, d), 7.38 (3H, br), 8.17 (1H, d), 8.23 (2H, d), 9.26 (2H,br), 9.43 (2H, br)

EXAMPLE 14 Synthesis ofN-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(1-acetimidoyl-4-piperidyloxy)benzamidebistrifluoroacetate

Step 1: Synthesis of 4-benzyloxy-3-hydroxybenzonitrile

1.0 g (7.41 mmol) of 3,4-dihydroxybenzonitrile was dissolved in 10 ml ofN,N-dimethylformamide. 1.12 g (8.15 mmol) of potassium carbonate and0.88 ml (7.41 mmol) of benzyl bromide were added to the obtainedsolution, and they were stirred at 50° C. for 2 hours. After thetreatment with ethyl acetate as the extraction solvent in an ordinarymanner, the solvent was evaporated, and the obtained residue waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 1.06 g (4.71 mmol) (64%)

H-NMR (CDCl3) δ 5.17 (2H, s), 6.95 (1H, d), 7.18 (1H, d), 7.20 (1H, d),7.41 (5H, br)

Step 2: Synthesis of4-benzyloxy-3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile

8.0 g (35.7 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in 20ml of DMF. 4.0 g (17.7 mmol) of 4-benzyloxy-3-hydroxybenzonitrile and7.4 g (41.3 mmol) of potassium carbonate were added to the obtainedsolution, and they were stirred at 100° C. for 3 hours. After thetreatment with ethyl acetate as the extraction solvent in an ordinarymanner, the solvent was evaporated, and the obtained residue waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 3.4 g (9.2 mmol) (52%)

H-NMR (CDCl3) δ 1.46 (9H, s), 3.74 (2H, dt), 4.11 (2H, t), 5.15 (2H, d),7.18 (1H, d), 7.20 (1H, d), 7.41 (5H, br)

Step 3: Synthesis of 3-(2-aminoethoxy)-4-benzyloxybenzonitrile

3.4 g (9.2 mmol) of4-benzyloxy-3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile wasdissolved in 40 ml of 4 N solution of hydrogen chloride in dioxane, andthe obtained solution was stirred overnight. The solvent was evaporatedto obtain hydrochloride of the crude title compound.

Yield: 3.0 g

Step 4: Synthesis ofN-[2-(5-cyano-2-benzyloxyphenoxy)ethyl]-4-(1-t-butoxycarbonyl-4-piperidyloxy)benzamide

1.06 g (3.50 mmol) of 3-(2-aminoethoxy)-4-benzyloxybenzonitrilehydrochloride was dissolved in 15 ml of DMF. 1.23 g (3.84 mmol) of4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 710 mg (4.2 mmol)) of2-chloro-1,3-dimethylimidazonium chloride and 1.45 ml (5.19 mmol) oftriethylamine were added to the obtained solution, and they were stirredovernight. After the treatment with dichloromethane as the extractionsolvent in an ordinary manner, the solvent was evaporated, and theobtained residue was purified by the silica gel column chromatography toobtain the title compound.

Yield: 510 mg (0.89 mmol) (26%)

H-NMR (CDCl3) δ 1.47 (9H, s), 1.66-1.80 (2H, m), 1.83-1.97 (2H, m),3.25-3.41 (2H, m), 3.61-3.73 (2H, m), 3.84 (2H, dt), 4.20 (2H, t),4.44-4.53 (1H, m), 5.16 (2H, d), 6.62 (1H, t), 6.84 (2H, d), 6.95 (1H,d), 7.15 (1H, d), 7.24 (1H, d), 7.28-7.42 (5H, m), 7.65 (2H, d)

Step 5: Synthesis ofN-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(4-piperidyloxy)benzamidebistrifluoroacetate

510 mg (0.89 mmol) ofN-[2-(5-cyano-2-benzyloxyphenoxy)ethyl]-4-(1-t-butoxycarbonyl-4-piperidyloxy)benzamidewas dissolved in a mixture of 5 ml of 4 N solution of hydrogen chloridein dioxane and 1 ml of ethanol, and the obtained solution was stirredfor 3 days. The solvent was evaporated, and the obtained crude productwas dissolved in 10 ml of ethanol. 500 mg of ammonium carbonate wasadded to the obtained solution, and they were stirred overnight. Thesolvent was evaporated, and the obtained crude product was dissolved in10 ml of ethanol. 50 mg of 10% palladium/carbon was added to theobtained solution, and they were stirred in the presence of hydrogenovernight. The reaction solution was filtered through Celite. Thesolvent was evaporated, and the obtained crude product was treated inthe same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 300 mg (0.479 mmol) (54%)

MS (ESI,m/z) 399 (MH+)

H-NMR (DMSO) δ 1.68-1.87 (2H, m), 2.03-2.17 (2H, m), 3.02-3.16 (2H, m),3.19-3.30 (2H, m), 3.65 (2H, dt), 4.14 (2H, t), 4.46-4.78 (1H, m), 6.95(1H, d), 7.05 (2H, d), 7.36 (1H, d), 7.42 (1H, br), 7.82 (2H, d), 8.57(1H, br), 8.84 (2H, br), 9.02 (2H, br)

Step 6: Synthesis ofN-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(1-acetimidoyl-4-piperidyloxy)benzamidebistrifluoroacetate

300 mg (0.479 mmol) ofN-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-4-(4-piperidyloxy)benzamidebistrifluoroacetate was dissolved in 10 ml of ethanol. 500 mg (5.3 mmol)of ethyl acetimidate and 0.5 ml (3.5 mmol) of triethylamine were addedto the obtained solution, and they were stirred at room temperatureovernight. The solvent was evaporated, and the obtained crude productwas treated in the same manner as that in step 9 in Example 1 to obtainthe title compound.

Yield: 220 mg (0.33 mmol) (69%)

MS (ESI,m/z) 440 (MH+)

H-NMR (DMSO) δ 1.63-1.84 (2H, m), 1.99-2.10 (2H, m), 2.27 (1H, s),3.40-3.56 (4H, m), 3.65 (2H, dt), 3.66-3.81 (2H, m), 4.14 (2H, t),4.66-4.87 (1H, m), 6.96 (1H, d), 7.06 (2H, d), 7.37 (1H, d), 7.42 (1H,br), 7.82 (2H, d), 8.58 (1H, t), 8.62 (1H, br), 8.94 (2H, br), 9.03 (2H,br), 9.16 (1H, br)

EXAMPLE 15 Synthesis ofN-[2-(5-amidino-2-hydroxyphenoxy)ethyl]-1-(4-pyridyl)-4-piperidine-4-carboxamidebistrifluoroacetate

1.00 g (3.30 mmol) of 3-(2-aminoethoxy)-4-benzyloxybenzonitrilehydrochloride was dissolved in 15 ml of DMF. 876 mg (3.62 mmol) of1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 837 mg (4.95mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.4 ml (9.9 mmol)of triethylamine were added to the obtained solution, and they werestirred overnight. After the treatment with dichloromethane as theextraction solvent in an ordinary manner, the solvent was evaporated,and the obtained residue was dissolved in a mixture of 10 ml of 4 Nsolution of hydrogen chloride in dioxane and 2 ml of ethanol. Theobtained solution was stirred for 3 days. The solvent was evaporated,and the obtained crude product was dissolved in 10 ml of ethanol. 500 mgof ammonium carbonate was added to the solution, and they were stirredovernight. The solvent was evaporated, and the obtained crude productwas dissolved in 10 ml of ethanol. 50 mg of 10% palladium/carbon wasadded to the obtained solution, and they were stirred in the presence ofhydrogen overnight. The reaction solution was filtered through Celite.The solvent was evaporated and the residue was treated in the samemanner as that in step 9 in Example 1 to obtain the title compound.

Yield: 50 mg (0.082 mmol) (3%)

MS (ESI,m/z) 383 (MH+)

H-NMR (DMSO) δ 1.46-1.64 (2H, m), 1.75-1.91 (2H, m), 2.48-2.55 (2H, m),3.04-3.26 (2H, m), 3.46 (2H, dt), 4.04 (2H, t), 4.17-4.29 (1H, m), 6.96(1H, d), 7.12 (1H, d), 7.18 (2H, d), 7.27 (1H, br), 8.19 (1H, t), 8.20(2H, d), 8.95 (1H, br), 8.98 (1H, br), 9.03 (1H, br), 9.05 (1H, br)

EXAMPLE 16 Synthesis of3-[4-amidino-2-(3-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)propoxy)phenyl]propionicacid bistrifluoroacetate

Step 1: Synthesis of t-butyl (3-bromopropyl)carbamate

The title compound was obtained from 18.4 g (84.2 mmol) of3-bromopropylamine hydrobromide and 13.1 g (60 mmol) of di-t-butyldicarbonate in the same manner as that in step 5 in Example 1 to obtainthe title compound.

Yield: 11.8 g (50.0 mmol) (83%)

H-NMR (CDCl3) δ 1.42 (9H, s), 2.05 (2H, tt), 3.25 (2H, dt), 3.45 (2H,t), 4.70 (1H, br)

Step 2: Synthesis of3-[3-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile

10.0 g (42 mmol) of t-butyl (3-bromopropyl))carbamate was dissolved in100 ml of DMF. 5.1 g (21 mmol) of 3-hydroxy-4-iodobenzonitrile and 8.7 g(41.3 mmol) of potassium carbonate were added to the obtained solution,and they were stirred at 100° C. for 2 hours. After the treatment withethyl acetate as the extraction solvent in an ordinary manner, theobtained crude product was purified by the silica gel columnchromatography to obtain the title compound.

Yield: 8.2 g (20.4 mmol) (98%)

H-NMR (CDCl3) δ 1.46 (9H, s), 2.04 (2H, tt), 3.39 (2H, t), 4.12 (2H, t),6.98 (2H, br), 7.88 (1H, d).

Step 3: Synthesis of ethyl3-[2-(3-(t-butoxycarbonylamino)propoxy)-4-cyanophenyl]acrylate

4.5 g (11.2 mmol) of3-[3-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in20 ml of DMF. 6.0 ml (56 mmol) of ethyl acrylate, 6.2 ml (56 mmol) oftriethylamine and 56 mg (0.22 mmol) of palladium acetate were added tothe obtained solution, and they were stirred at 100° C. overnight. Afterthe treatment with ethyl acetate as the extraction solvent in anordinary manner, the obtained crude product was purified by the silicagel column chromatography to obtain the title compound.

Yield: 3.8 g (10.2 mmol) (91%)

H-NMR (CDCl3) δ 1.33 (3H, t), 1.43 (9H, s), 2.08 (2H, tt), 3.37 (2H,dt), 4.11 (2H, t), 4.26 (2H, q), 6.54 (1H, d), 7.14 (1H, br), 7.24 (1H,d), 7.56 (1H, d), 7.91 (1H, d)

Step 4: Synthesis of ethyl3-[2-(3-aminopropoxy)-4-cyanophenyl]propionate

3.8 g (10.2 mmol) of ethyl3-[2-(3-(t-butoxycarbonylamino)propoxy)-4-cyanophenyl]acrylate wasdissolved in 100 ml of ethyl acetate. 700 mg of 10% palladium/carbon(50% hydrous) was added to the obtained solution, and they were stirredin the presence of hydrogen for 3 hours. The reaction solution wasfiltered through Celite. The solvent was evaporated, and the obtainedcrude product was dissolved in 50 ml of 4 N solution of hydrogenchloride in dioxane. The obtained solution was stirred overnight. Thesolvent was evaporated to obtain hydrochloride of the crude titlecompound.

Yield: 2.4 g (7.5 mmol) (74%)

Step 5: Synthesis of3-[4-cyano-2-(3-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)propoxy)phenyl]propionicacid bistrifluoroacetate

1.06 g (3.33 mmol) of ethyl3-[2-(3-aminopropoxy)-4-cyanophenyl]propionate hydrochloride wasdissolved in 10 ml of DMF. 887 mg (3.6 mmol) of1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 844 mg (5.0mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.4 ml (9.9 mmol)of triethylamine were added to the obtained solution, and they werestirred overnight. The solvent was evaporated, and the obtained crudeproduct was dissolved in a mixture of 20 ml of 4 N solution of hydrogenchloride in dioxane and 4 ml of ethanol, and they were stirred for 3days. The solvent was distilled off, and the obtained crude product wasdissolved in 20 ml of ethanol. 1000 mg of ammonium carbonate was addedto the obtained solution, and they were stirred overnight. The solventwas evaporated, and the obtained crude product was dissolved in 10 ml of6 N aqueous hydrochloric acid solution, and the obtained solution wasstirred at 50° C. for 2 hours. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 660 mg (0.97 mmol) (29%)

MS (ESI,m/z) 454 (MH+)

H-NMR (DMSO-d6) δ 1.46-1.66 (2H, m), 1.46-1.98 (4H, m), 2.48 (2H, br),2.52 (2H, t), 2.85 (2H, t), 3.18-3.27 (4H, m), 4.08 (2H, t), 4.20 (1H,br), 7.17 (1H, d), 7.32 (2H, d), 7.36 (1H, d), 8.00 (1H, t), 8.19 (2H,d), 9.20 (2H, br) 9.24 (2H, br)

EXAMPLE 17 Synthesis of3-[4-amidino-2-(2-((1-(2,3,5,6-tetrafluoropyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate:

Step 1: Synthesis of ethyl1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-piperidinecarboxylate

1.1 g (6.5 mmol) of pentafluoropyridine, 1.1 g (6.5 mmol) of ethylpiperidine-4-carboxylate and 2.27 ml (13.7 mmol) ofdiisopropylethylamine were stirred in 5 ml of ethanol at roomtemperature for 24 hours. After the treatment with ethyl acetate as theextraction solvent in an ordinary manner, the obtained crude product waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 2.0 g (6.5 mmol) (100%)

H-NMR (CDCl3) δ 1.25 (3H, t), 1.78-1.93 (2H, m), 1.98-2.09 (2H, m),2.46-2.60 (1H, m) 3.25 (2H, t), 3.69 (2H, d), 4.17 (2H, q)

Step 2: Synthesis of1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-piperidinecarboxylic acidhydrochloride

2.0 g (6.5 mmol) of ethyl1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-piperidinecarboxylate was stirredin 5 ml of dioxane. 5 ml of 2 N hydrochloric acid was added to theobtained mixture, and they were stirred at 95° C. for 2 hours. Thesolvent was evaporated to obtain the crude title compound.

Yield: 1.5 g (4.7 mmol) (73%)

Step 3: Synthesis of3-[4-amidino-2-(2-((1-(2,3,5,6-tetrafluoropyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

600 mg (2.15 mmol) of ethyl3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride wasdissolved in 10 ml of DMF. 812 mg (2.6 mmol) of1-(2,3,5,6-tetrafluoropyridyl-4-yl)-4-piperidinecarboxylic acidhydrochloride, 560 mg (3.3 mmol) of 2-chloro-1,3-dimethylimidazoniumchloride and 0.9 ml (6.5 mmol) of triethylamine were added to theobtained solution, and they were stirred overnight. The solvent wasevaporated, and the obtained crude product was dissolved in a mixture of5 ml of 4 N solution of hydrogen chloride in dioxane and 1 ml ofethanol, and they were stirred for 3 days. The solvent was distilledoff, and the obtained crude product was dissolved in 20 ml of ethanol.500 mg of ammonium carbonate was added to the obtained solution, andthey were stirred overnight. The solvent was evaporated, and theobtained crude product was dissolved in 10 ml of 6 N aqueoushydrochloric acid solution, and the obtained solution was stirred at 50°C. for 2 hours. The solvent was evaporated, and the obtained crudeproduct was treated in the same manner as that in step 9 in Example 1 toobtain the title compound.

Yield: 100 mg (0.14 mmol) (5%)

MS (ESI,m/z) 512 (MH+)

H-NMR (DMSO-d6) δ 1.58-1.81 (4H, m), 2.33-2.41 (1H, m), 2.54 (2H, t),2.86 (2H, t), 3.12-3.23 (2H, m), 3.47 (2H, t), 3.66 (2H, d), 4.11 (2H,t), 7.31-7.38 (3H, d), 8.13 (1H, t), 9.00 (2H, br), 9.22 (2H, br)

EXAMPLE 18 Synthesis of3-[4-amidino-2-(2-((1-(pyridine-4-ylmethyl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

Step 1: Synthesis of ethyl1-(pyridyl-4-ylmethyl)-4-piperidinecarboxylate

1.15 g (7.0 mmol) of picolyl chloride hydrochloride, 1.0 g (6.4 mmol) ofethyl piperidine-4-carboxylate and 1.3 ml (9.6 mmol) of triethylaminewere stirred in 10 ml of DMF at room temperature for 4 hours. After thetreatment with ethyl acetate as the extraction solvent in an ordinarymanner, the obtained crude product was purified by the silica gel columnchromatography to obtain the title compound.

Yield: 1.0 g (3.51 mmol) (55%)

H-NMR (CDCl3) δ 1.25 (3H, t), 1.64-1.96 (4H, m), 2.02-2.17 (2H, m),2.22-2.40 (1H, m) 2.80 (2H, d), 3.49 (2H, s), 4.13 (2H, q)

Step 2: Synthesis of3-[4-amidino-2-(2-((1-(pyridine-4-ylmethyl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

1.0 g (3.51 mmol) of ethyl1-(pyridyl-4-ylmethyl)-4-piperidinecarboxylate was stirred in 10 ml ofdioxane. 10 ml of 2 N hydrochloric acid was added to the obtainedmixture, and they were stirred at 95° C. for 4 hours. The solvent wasevaporated, and the obtained crude product was dissolved in 10 ml ofDMF. 812 mg (2.9 mmol) of ethyl3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 735 mg(4.35 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.2 ml (8.7mmol) of triethylamine were added to the obtained solution, and theywere stirred overnight. The solvent was evaporated, and the obtainedcrude product was dissolved in a mixture of 5 ml of 4 N solution ofhydrogen chloride in dioxane and 1 ml of ethanol, and the obtainedsolution was stirred for 3 days. The solvent was evaporated, and theobtained crude product was dissolved in 20 ml of ethanol. 500 mg ofammonium carbonate was added to the obtained solution, and they werestirred overnight. The solvent was evaporated, then the obtained crudeproduct was dissolved in 10 ml of 6 N aqueous hydrochloric acidsolution, and the obtained solution was stirred at 50° C. for 2 hours.The solvent was evaporated, and the obtained crude product was treatedin the same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 70 mg (0.10 mmol) (3%)

MS (ESI,m/z) 454(MH+)

H-NMR (DMSO-d6) δ 1.65-1.96 (4H, m), 2.27-2.58 (3H, m), 2.73-3.10 (4H,m), 3.29-3.56 (4H, m), 4.09 (2H, t), 4.35 (2H, br), 7.35 (3H, br), 7.56(2H, d), 8.25 (1H, t), 8.70 (2H, d), 9.16 (2H, br), 9.22 (2H, br)

EXAMPLE 19 Synthesis of3-[4-amidino-2-(2-((1-(pyridine-4-carbonyl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

Step 1: Synthesis of ethyl1-(pyridyl-4-carbonyl)-4-piperidinecarboxylate

1.25 g (7.0 mmol) of isonicotinoyl chloride hydrochloride, 1.0 g (6.4mmol) of ethyl piperidine-4-carboxylate and 1.3 ml (9.6 mmol) oftriethylamine were stirred in 10 ml of DMF at room temperature for 4hours. After the treatment with ethyl acetate as the extraction solventin an ordinary manner, the obtained crude product was purified by thesilica gel column chromatography to obtain the title compound.

Yield: 850 mg (2.84 mmol) (44%)

H-NMR (CDCl3) δ 1.27 (3H, t), 1.60-2.09 (4H, m), 2.02-2.17 (2H, m),2.50-2.68 (1H, m) 3.06 (2H, d), 3.60 (1H, d), 4.18 (2H, q), 4.50 (2H,d),

Step 2: Synthesis of3-[4-amidino-2-(2-((1-(pyridine-4-carbonyl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

850 mg (2.84 mmol) of ethyl1-(pyridyl-4-carbonyl)-4-piperidinecarboxylate was stirred in 10 ml ofdioxane. 10 ml of 2 N hydrochloric acid was added to the obtainedmixture, and they were stirred at 95° C. for 4 hours. The solvent wasevaporated, and the obtained crude product was dissolved in 10 ml ofDMF. 700 mg (2.5 mmol) of ethyl3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 634 mg(3.75 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.74 ml(7.5 mmol) of triethylamine were added to the obtained solution, andthey were stirred overnight. The solvent was evaporated, and theobtained crude product was dissolved in a mixture of 5 ml of 4 Nsolution of hydrogen chloride in dioxane and 1 ml of ethanol, and theywere stirred for 3 days. The solvent was evaporated, and the obtainedcrude product was dissolved in 20 ml of ethanol. 500 mg of ammoniumcarbonate was added to the obtained solution, and they were stirredovernight. The solvent was evaporated, and the obtained crude productwas dissolved in 10 ml of 6 N aqueous hydrochloric acid solution, andthe obtained solution was stirred at 50° C. for 2 hours. The solvent wasevaporated, and the obtained crude product was treated in the samemanner as that in step 9 in Example 1 to obtain the title compound.

Yield: 100 mg (0.15 mmol) (5%)

MS (ESI,m/z) 454(MH+)

H-NMR (DMSO-d6) δ 1.37-1.84 (4H, m), 2.27-2.56 (3H, m), 2.73-3.13 (4H,m), 3.29-3.56 (3H, m), 4.09 (2H, t), 4.42 (1H, d), 7.21-7.33 (5H, m),8.10 (1H, t), 8.67 (2H, d), 8.94 (2H, br), 9.21 (2H, br)

EXAMPLE 20 Synthesis of3-[4-amidino-2-(2-((1-(3,5-dichloropyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

Step 1: Synthesis of ethyl1-(3,5-dichloropyridine-4-yl)-4-piperidinecarboxylate

2.0 g (11 mmol) of 3,4,5-trichloropyridine, 1.7 g (11 mmol) of ethylpiperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine werestirred in 20 ml of xylene under heating under reflux for 10 hours.After the treatment with ethyl acetate as the extraction solvent in anordinary manner, the obtained crude product was purified by the silicagel column chromatography to obtain the title compound.

Yield: 800 mg (2.6 mmol) (24%)

H-NMR (CDCl3) δ 1.28 (3H, t), 1.80-2.03 (4H, m), 2.44-2.58 (1H, m),3.23-3.44 (4H, m), 4.17 (2H, q), 8.32 (2H, s)

Step 2: Synthesis of ethyl3-[4-cyano-2-(2-((1-(3,5-dichloropyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionate

2.0 g (6.5 mmol) of ethyl1-(3,5-dichloropyridine-4-yl)-4-piperidinecarboxylate was stirred in 5ml of dioxane. 5 ml of 2 N hydrochloric acid was added to the obtainedmixture, and they were stirred at 95° C. for 4 hours. The solvent wasevaporated, and the obtained crude product was dissolved in 10 ml ofDMF. 612 mg (2.27 mmol) of ethyl3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 575 mg(3.40 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.9 ml (6.8mmol) of triethylamine were added to the obtained solution, and theywere stirred overnight. After the treatment with ethyl acetate as theextraction solvent in an ordinary manner, the obtained crude product waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 1.0 g (1.9 mmol) (73%)

H-NMR (CDCl3) δ 1.21 (3H, t), 1.83-2.06 (4H, m), 2.31-2.43 (2H, m),2.46-2.60 (1H, m), 2.62 (2H, t), 3.00 (2H, t), 3.22-3.41 (4H, m), 3.73(2H, dt), 4.03-4.11 (4H, m), 7.04 (1H, br), 7.22 (2H, d), 8.32 (2H, s)

Step 3: Synthesis of3-[4-amidino-2-(2-((1-(3,5-dichloropyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

1.0 g (1.9 mmol) of ethyl3-[4-cyano-2-(2-((1-(3,5-dichloropyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionatewas dissolved in a mixture of 10 ml of 4 N solution of hydrogen chloridein dioxane and 2 ml of ethanol, and they were stirred for 3 days. Thesolvent was evaporated, and the obtained crude product was dissolved in20 ml of ethanol. 500 mg of ammonium carbonate was added to the obtainedsolution, and they were stirred overnight. The solvent was evaporated,and the obtained crude product was dissolved in 10 ml of 6 N aqueoushydrochloric acid solution, and the obtained solution was stirred at 50°C. for 2 hours. The solvent was evaporated, and the obtained crudeproduct was treated in the same manner as that in step 9 in Example 1 toobtain the title compound.

Yield: 280 mg (0.38 mmol) (20%)

MS (ESI,m/z) 508 (MH+)

H-NMR (DMSO-d6) δ 1.62-1.78 (4H, m), 2.16-2.22 (1H, m), 2.52 (2H, t),2.87 (2H, t), 3.18-3.27 (4H, m), 3.46 (2H, t), 4.12 (2H, t), 7.30-7.41(3H, m), 8.12 (1H, t), 8.41 (2H, s), 8.98 (2H, br), 9.22 (2H, br)

EXAMPLE 21 Synthesis of3-[4-amidino-2-(2-((4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl)amino)ethoxy)phenyl]propionic acid bistrifluoroacetate

Step 1: Synthesis of ethyl 4-methyl-2-(4-pyridyl)thiazole-5-carboxylate

2.76 g (20 mmol) of thioisonicotinamide and 3.6 g (22 mmol) of ethyl2-chloroacetacetate were heated under reflux in 30 ml of ethanol for 20hours. After the treatment with ethyl acetate as the extraction solventin an ordinary manner, the obtained crude product was purified by thesilica gel column chromatography to obtain the title compound.

Yield: 2.0 g (8.1 mmol) (40%)

H-NMR (CDCl3) δ 1.40 (3H, t), 2.81 (3H, s), 4.38 (2H, q), 7.81 (2H, d),8.73 (2H, d)

Step 2: Synthesis of ethyl3-[4-cyano-2-(2-((4-methyl-2-pyridyl-4-yl-thiazole-5-carbonyl)amino)ethoxy)phenyl]propionate

1.58 g (6.37 mmol) of ethyl 4-methyl-2-(4-pyridyl)thiazole-5-carboxylatewas stirred in 5 ml of ethanol. 5 ml of 1 N sodium hydroxide was addedto the obtained mixture, and they were stirred at room temperature for 4hours. 5 ml of 1 N hydrochloric acid was added to the reaction mixture.A portion (700 mg) of the obtained crystals was dissolved in 10 ml ofDMF. 590 mg (2.12 mmol) of ethyl3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 539 mg(3.19 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.3 ml(9.57 mmol) of triethylamine were added to the obtained solution, andthey were stirred overnight. After the treatment with ethyl acetate asthe extraction solvent in an ordinary manner, the obtained crude productwas purified by the silica gel column chromatography to obtain the titlecompound.

Yield: 600 mg (1.29 mmol)

H-NMR (CDCl3) δ 1.15 (3H, t), 2.61 (2H, t), 3.01 (2H, t), 3.92 (2H, dt),4.03 (2H, q), 4.20 (2H, t), 7.07 (1H, br), 7.25 (2H, d), 7.80 (2H, d),8.73 (2H, d)

Step 3: Synthesis of3-[4-amidino-2-(2-((4-methyl-2-pyridyl-4-ylthiazole-5-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

600 mg (1.29 mmol) of ethyl3-[4-cyano-2-(2-((4-methyl-2-pyridyl-4-yl-thiazole-5-carbonyl)amino)ethoxy)phenyl]propionate was dissolved in a mixture of 10 ml of 4N hydrogen chloride in dioxane and 2 ml of ethanol, and they werestirred for 3 days. The solvent was evaporated, and the obtained crudeproduct was dissolved in 20 ml of ethanol. 500 mg of ammonium carbonatewas added to the obtained solution, and they were stirred overnight. Thesolvent was evaporated, and the obtained crude product was dissolved in10 ml of 6 N aqueous hydrochloric acid solution, and the obtainedsolution was stirred at 50° C. for 2 hours. The solvent was evaporated,and the obtained crude product was treated in the same manner as that instep 9 in Example 1 to obtain the title compound.

Yield: 300 mg (0.44 mmol) (34%)

MS (ESI,m/z) 454(MH+)

H-NMR (DMSO-d6) δ 2.53 (2H, t), 2.63 (3H, s), 2.88 (2H, t), 3.68 (2H,dt), 4.23 (2H, t), 7.32-7.41 (3H, m), 7.88 (2H, d), 8.66 (1H, t), 8.73(2H, d), 9.05 (2H, br), 9.23 (2H, br)

EXAMPLE 22 Synthesis of3-[4-amidino-2-(2-((1-(6-chloropyridazine-3-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

Step 1: Synthesis of ethyl1-(6-chloropyridazine-3-yl)-4-piperidinecarboxylate

2.0 g (13.4 mmol) of 3,6-dichloropyridazine, 2.3 g (14.8 mmol) of ethylpiperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine werestirred in 20 ml of DMF at 50° C. for 4 hours. After the treatment withethyl acetate as the extraction solvent in an ordinary manner, theobtained crude product was purified by the silica gel columnchromatography to obtain the title compound.

Yield: 1.58 g (5.86 mmol) (44%)

H-NMR (CDCl3) δ 1.26 (3H, t), 1.71-1.88 (2H, m), 1.97-2.06 (2H, m),2.50-2.64 (1H, m), 3.03-3.17 (2H, m), 4.16 (2H, q), 4.23 (2H, dt), 6.91(1H, d), 7.18 (1H, d)

Step 2: Synthesis of3-[4-amidino-2-(2-((1-(6-chloropyridazine-3-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

600 mg (2.22 mmol) of ethyl1-(6-chloropyridazine-3-yl)-4-piperidinecarboxylate was stirred in 5 mlof dioxane. 5 ml of 2 N hydrochloric acid was added to the obtainedmixture, and they were stirred at 95° C. for 4 hours. The solvent wasevaporated, and the obtained crude product was dissolved in 10 ml ofDMF. 514 mg (1.85 mmol) of ethyl3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 470 mg(2.78 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.77 ml(5.58 mmol) of triethylamine were added to the obtained solution, andthey were stirred overnight. After the treatment with ethyl acetate asthe extraction solvent in an ordinary manner, the obtained crude productwas dissolved in a mixture of 10 ml of 4 N solution of hydrogen chloridein dioxane and 2 ml of ethanol, and they were stirred for 3 days. Thesolvent was evaporated, and the obtained crude product was dissolved in20 ml of ethanol. 500 mg of ammonium carbonate was added to the obtainedsolution, and they were stirred overnight. The solvent was evaporated,then the obtained crude product was dissolved in 10 ml of 6 N aqueoushydrochloric acid solution, and the obtained solution was stirred at 50°C. for 2 hours. The solvent was evaporated, and the obtained crudeproduct was treated in the same manner as that in step 9 in Example 1 toobtain the title compound.

Yield: 280 mg (0.40 mmol) (18%)

MS (ESI,m/z) 475 (MH+)

H-NMR (DMSO-d6) δ 1.43-1.62 (2H, m), 1.70-1.82 (2H, m), 2.37-2.60 (3H,m), 2.77-3.01 (4H, m), 3.47 (2H, dt), 4.27 (2H, t), 4.32 (2H, d),7.23-7.42 (4H, m), 7.49 (1H, d), 8.14 (1H, t), 8.99 (2H, br), 9.24 (2H,br)

EXAMPLE 23 Synthesis of3-[4-amidino-2-(2-((1-pyridazine-3-yl)piperidine-4-carboxyl)amino)ethoxy)phenyl]propionamidebistrifluoroacetate

150 mg (0.21 mmol) of3-[4-amidino-2-(2-((1-(6-chloropyridazine-3-yl)piperizine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate was dissolved in 10 ml of ethanol. 10 mg ofPd-C was added to the obtained solution, and they were stirred in thepresence of hydrogen at room temperature for 4 hours. The reactionsolution was filtered through Celite, and the obtained crude product wastreated in the same manner as that in step 9 in Example 1 to obtain thetitle compound.

Yield: 50 mg (0.075 mmol) (36%)

MS (ESI,m/z) 441 (MH+)

H-NMR (DMSO-d6) δ 1.50-1.63 (2H, m), 1.77-1.91 (2H, m), 2.51 (2H, t),2.84 (2H, t), 3.00-3.19 (2H, m), 3.39-3.58 (1H, m), 3.46 (2H, dt), 4.08(2H, t), 4.27 (2H, d), 7.32 (1H, d), 7.34 (1H, d), 7.75 (1H, br), 8.15(1H, t), 8.61 (1H, d), 9.05 (2H, br), 9.22 (2H, br)

EXAMPLE 24 Synthesis of3-[4-amidino-2-(2-((1-(2-chloropyrimidine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

Step 1: Synthesis of ethyl1-(2-chloropyrimidine-4-yl)-4-piperidinecarboxylate

2.0 g (13.4 mmol) of 2,4-dichloropyrimidine, 2.32 g (14.7 mmol) of ethylpiperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine werestirred in 20 ml of DMF at 50° C. for 4 hours. After the treatment withethyl acetate as the extraction solvent in an ordinary manner, theobtained crude product was purified by the silica gel columnchromatography to obtain the title compound.

Yield: 700 mg (2.60 mmol) (19%)

H-NMR (CDCl3) δ 1.26 (3H, t), 1.63-1.80 (2H, m), 1.92-2.09 (2H, m),2.52-2.66 (1H, m), 3.03-3.19 (2H, m), 4.11-4.37 (4H, m), 6.39 (1H, d),8.02 (1H, d)

Step 2: Synthesis of ethyl3-[4-cyano-2-(2-((1-(2-chloropyrimidine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionate

700 mg (2.60 mmol) of ethyl1-(2-chloropyridine-4-yl)-4-piperidinecarboxylate was stirred in 5 ml ofdioxane. 5 ml of 2 N hydrochloric acid was added to the obtainedmixture, and they were stirred at 95° C. for 4 hours. The solvent wasevaporated, and the obtained crude product was dissolved in 10 ml ofDMF. 600 mg (2.16 mmol) of ethyl3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 548 mg(3.24 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.9 ml(6.48 mmol) of triethylamine were added to the obtained solution, andthey were stirred overnight. After the treatment with ethyl acetate asthe extraction solvent in an ordinary manner, the obtained crude productwas purified by the silica gel column chromatography to obtain the titlecompound.

Yield: 320 mg (0.66 mmol) (31%)

H-NMR (CDCl3) δ 1.25 (3H, t), 1.63-2.05 (4H, m), 2.60 (2H, t), 2.99 (2H,t), 3.00-3.21 (3H, m), 3.68 (2H, dt), 4.07 (2H, t), 4.15 (2H, q),4.18-4.41 (2H, m), 6.38 (1H, d), 7.02 (1H, bs), 7.23 (1H, bs), 8.00 (2H,br)

Step 3: Synthesis of3-[4-amidino-2-(2-((1-(2-chloropyrimidine-4-yl)piperidine-4-carbonyl)amino)ethoxy]phenyl]propionicacid bistrifluoroacetate

320 mg (0.66 mmol) of ethyl3-[4-cyano-2-(2-((1-(2-chloropyrimidine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionatewas dissolved in a mixture of 10 ml of 4 N solution of hydrogen chloridein dioxane and 2 ml of ethanol, and they were stirred for 3 days. Thesolvent was evaporated, and the obtained crude product was dissolved in20 ml of ethanol. 500 mg of ammonium carbonate was added to the obtainedsolution, and they were stirred overnight. The solvent was evaporated,and the obtained crude product was dissolved in 10 ml of 6 N aqueoushydrochloric acid solution, and the obtained solution was stirred at 50°C. for 2 hours. The solvent was evaporated, and the obtained crudeproduct was treated in the same manner as that in step 9 in Example 1 toobtain the title compound.

Yield: 50 mg (0.071 mmol) (11%)

MS (ESI,m/z) 475 (MH+)

H-NMR (DMSO-d6) δ 1.37-1.58 (2H, m), 1.63-2.01 (2H, m), 2.54 (2H, t),2.86 (2H, t), 2.94-3.24 (3H, m), 3.46 (2H, dt), 4.08 (2H, t), 4.20 (2H,br), 6.81 (1H, d), 7.32 (1H, d), 7.34 (2H, d), 8.03 (1H, d), 8.13 (1H,t), 8.98 (2H, br), 9.21 (2H, br)

EXAMPLE 25 Synthesis of3-[4-amidino-2-(2-((1-(pyrimidine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

50 mg (0.071 mmol) of3-[4-amidino-2-(2-((1-(2-chloropyrimidine-4yl)piperizine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate was dissolved in 5 ml of ethanol. 10 mg ofpalladium/carbon was added to the obtained solution, and they werestirred in the presence of hydrogen at room temperature for 4 hours. Thereaction solution was filtered through Celite, the solvent wasevaporated and the obtained crude product was treated in the same manneras that in step 9 in Example 1 to obtain the title compound.

Yield: 18 mg (0.027 mmol) (38%)

MS (ESI,m/z) 441 (MH+)

H-NMR (DMSO-d6) δ 1.42-1.61 (2H, m), 1.70-1.91 (2H, m), 2.54 (2H, t),2.85 (2H, t), 3.03-3.24 (3H, m), 3.46 (2H, dt), 4.08 (2H, t), 4.46 (2H,br), 7.17 (1H, dd), 7.34 (2H, d), 7.38 (1H, dd), 8.18 (3H, br), 9.18(2H, br), 9.22 (2H, br)

EXAMPLE 26 Synthesis of3-[4-amidino-(2R)-2-((1-(pyridine-4-yl)piperidine-4-carbonyl)pyrrolidine-2-ylmethoxy)phenyl]propionicacid bistrifluoroacetate

Step 1: Synthesis of1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidine

1 g of D-prolinol was dissolved in 24 ml of dioxane. 2.4 g (10.5 mmol)of di-t-butyl carbanate and 5.3 ml of 2 M aqueous sodium hydroxidesolution were added to the obtained solution under cooling with ice.They were stirred for 15 minutes and then at room temperature foradditional 2 hours. The solvent was evaporated, and the residue wastreated with ethyl acetate as the extraction solvent in an ordinarymanner to obtain the crude product. The crude product was dissolved in15 ml of dichloromethane. 2.23 g (10.8 mmol) of tosyl chloride and 1.5ml (10.5 mmol) of triethylamine were added to the obtained solution, andthey were stirred at room temperature overnight. After the treatment inan ordinary manner, the obtained crude product was purified by thesilica gel column chromatography to obtain the title compound.

Yield: 2.55 g (7.17 mmol), (72%)

H-NMR (CDCl3) δ 1.38 (9H,br), 1.70-2.00 (4H,m), 2.45 (3H,s), 3.30(2H,br), 3.90 (1H, br), 4.10 (2H,br), 7.32 (2H,d), 7.78 (2H,d).

Step 2: Synthesis of4-iodo-3-[(2R)-(1-t-butoxycarbonyl-pyrrolidine-2-ylmethoxy)]benzonitrile

2.0 g (8.16 mmol) of 3-hydroxy-4-iodobenzonitrile was dissolved in 20 mlof DMF. 5.8 g (16.3 mmol) of1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidineand 3.37 g (24.4 mmol) of potassium carbonate were added to the obtainedsolution, and they were stirred at 50° C. for 16 hours. 1.5 g (4.2 mmol)of1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidinewas added to the obtained mixture, and they were stirred at 50° C. for 4hours. After the treatment with ethyl acetate as the extraction solventin an ordinary manner, the obtained crude product was purified by thesilica gel column chromatography to obtain the title compound.

Yield: 3.7 g (8.6 mmol)

H-NMR (CDCl3) δ 1.47 (9H, s), 1.78-2.19 (4H, m), 3.22-3.34 (2H, m),3.83-4.04 (1H, m), 4.06-4.23 (2H, m), 3.03-3.41 (2H, m), 6.96 (1H, br),7.08 (1H, br), 7.88 (1H, br)

Step 3: Synthesis of ethyl3-[4-cyano-(2R)-2-(1-t-butoxycarbonylpyrrolidine-2-ylmethoxy)phenyl]acrylate

3.7 g (8.6 mmol) of4-iodo-3-[(2R)-(1-t-butoxycarbonyl-pyrrolidine-2-ylmethoxy)]benzonitrilewas dissolved in 40 ml of DMF. 4.68 ml (43 mmol) of ethyl acrylate , 6.1ml (43 mmol) of triethylamine and 194 mg (0.85 mmol) of palladiumacetate were added to the obtained solution, and they were stirred at100° C. overnight. After the treatment with ethyl acetate as theextraction solvent in an ordinary manner, the obtained crude product wastreated with ethyl acetate as the extraction solvent in an ordinarymanner to obtain the crude product, which was purified by the silica gelcolumn chromatography to obtain the title compound.

Yield: 3.0 g (7.5 mmol) (87%)

H-NMR (CDCl3) δ 1.34 (3H, t), 1.46 (9H, s), 1.90-2.17 (4H, m), 3.31-3.55(2H, m), 4.02-4.39 (3H, m), 4.27 (2H, q), 6.53 (1H, d), 7.13-7.28 (2H,m), 7.46-7.62 (1H, m), 7.93 (1H, d)

Step 4: Synthesis of ethyl3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmethoxy)phenyl]propionate

3.0 g (7.5 mmol) of ethyl3-[4-cyano-(2R)-2-(1-t-butoxycarbonyl-pyrrolidine-2-ylmethoxy)phenyl]acrylatewas dissolved in 20 ml of ethanol. 600 mg of 10% palladium/carbon (50%aqueous) was added to the obtained solution, and they were stirred inthe presence of hydrogen overnight. The reaction solution was filteredthrough Celite, and the solvent was evaporated. The obtained crudeproduct was dissolved in 10 ml of 4 N solution of hydrogen chloride indioxane, and the obtained solution was stirred at room temperature for 3hours. The solvent was evaporated to obtain hydrochloride of the titlecompound.

Yield: 1.8 g (6.0 mmol) (79%)

Step 5: Synthesis of ethyl3-[4-cyano-(2R)-2-((1-(pyridine-4-yl)piperidine-4-carbonyl)pyrrolidine-2-ylmethoxy)phenyl]propionate

570 mg (1.89 mmol) of ethyl3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmethoxy)phenyl]propionate wasdissolved in 10 ml of DMF. 504 mg (2.1 mmol) of1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 479 mg (2.8mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.78 ml (5.7mmol) of triethylamine were added to the obtained solution, and theywere stirred overnight.

Yield: 600 mg (1.22 mmol) (65%)

H-NMR (DMSO-d6) δ 1.24 (3H, t), 1.48-1.75 (2H, m), 1.78-1.94 (2H, m),1.95-2.20 (4H, m), 2.52-2.64 (3H, m), 2.80-3.03 (3H, m), 3.50-3.66 (2H,m), 3.82-4.00 (2H, m), 4.03-4.22 (4H, m), 4.40-4.52 (2H, m), 6.66 (2H,d), 7.11 (1H, br), 7.18-7.25 (2H, m), 8.24 (2H, d)

Step 6: Synthesis of3-[4-amidino-(2R)-2-((1-(pyridine-4-yl)piperidine-4-carbonyl)pyrrolidine-2-ylmethoxy)phenyl]propionicacid bistrifluoroacetate

600 g (1.22 mmol) of ethyl3-[4-cyano-(2R)-2-((1-(pyridine-4-yl)piperidine-4-carbonyl)pyrrolidine-2-ylmethoxy)phenyl]propionatewas dissolved in a mixture of 5 ml of 4 N solution of hydrogen chloridein dioxane and 1 ml of ethanol, and they were stirred for 3 days. Thesolvent was evaporated, and the obtained crude product was dissolved in20 ml of ethanol. 500 mg of ammonium carbonate was added to the obtainedsolution, and they were stirred overnight. The solvent was evaporated,and the obtained crude product was dissolved in 10 ml of 6 N aqueoushydrochloric acid solution. The obtained solution was stirred at 50° C.for 2 hours. The solvent was evaporated, and the obtained crude productwas treated in the same manner as that in step 9 in Example 1 to obtainthe title compound.

Yield: 190 mg (0.27 mmol) (22%)

MS (ESI,m/z) 480 (MH+)

H-NMR (DMSO-d6) δ 1.28-1.60 (2H, m), 1.77-2.16 (6H, m), 2.50 (2H, t),2.77-3.00 (3H, m), 3.16-3.30 (2H, m), 3.52-3.78 (2H, m), 4.06-4.29 (5H,m), 7.17 (2H, d), 7.34 (2H, d), 7.36 (1H, d), 8.19 (2H, t), 9.18 (2H,br), 9.21 (2H, br)

EXAMPLE 27 Synthesis of3-[4-amidino-(2R)-2-((1-(2-naphthalenesulfonyl)pyrrolidine-2-ylmethoxy)phenyl]propionicacid mono-trifluoroacetate

240 mg (0.79 mmol) of ethyl3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmethoxy)phenyl]propionatehydrochloride was dissolved in 10 ml of DMF. 271 mg (1.2 mmol) of2-naphthalenesulfonyl chloride and 0.22 ml (1.58 mmol) of triethylaminewere added to the obtained solution, and they were stirred overnight.The solvent was evaporated, and the obtained crude product was dissolvedin a mixture of 5 ml of 4 N solution of hydrogen chloride in dioxane and1 ml of ethanol, and the obtained solution was stirred for 3 days. thesolvent was evaporated, and the obtained crude product was dissolved in20 ml of ethanol. 200 mg of ammonium carbonate was added to the obtainedsolution, and they were stirred overnight. The solvent was evaporated,and the obtained crude product was dissolved in 10 ml of 6 N aqueoushydrochloric acid solution. The obtained solution was stirred at 50° C.for 2 hours. The solvent was evaporated, and the obtained crude productwas treated in the same manner as that in step 9 in Example 1 to obtainthe title compound.

Yield: 8 mg (0.013 mmol) (2%)

MS (ESI,m/z) 482 (MH+)

H-NMR (DMSO-d6) δ 1.41-1.77 (2H, m), 1.81-1.94 (2H, m), 2.50 (2H, t),2.80 (2H, t), 3.17-3.44 (3H, m), 4.03-4.36 (2H, m), 7.34 (1H, s), 7.36(2H, d), 7.69 (2H, dd), 7.88 (1H, d), 8.12 (2H, dd), 8.52 (1H, s), 8.96(2H, br), 9.26 (2H, br)

EXAMPLE 28 Synthesis of(3R)-4-(5-amidino-2-hydroxyphenoxy)-3-[4-(1-acetimidoyl-4-piperidyloxy)benzoylamino]butanoicacid bistrifluoroacetate

Step 1: Synthesis of benzyl(3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-benzyloxyphenoxy)butanoate

4.8 g (15.5 mmol) of benzyl(3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 mlof tetrahydrofuran. 2.9 g (12.9 mmol) of4-benzyloxy-3-hydroxybenzonitrile, 4.1 g (15.5 mmol) oftriphenylphosphine and 6.7 g (15.5 mmol) of diethyl azodicarboxylatewere added to the obtained solution under cooling with ice, and theywere stirred at room temperature overnight. After the treatment withethyl acetate as the extraction solvent in an ordinary manner, theobtained crude product was purified by the silica gel columnchromatography to obtain the title compound.

Yield: 3.7 g (7.2 mmol) (56%)

H-NMR (CDCl3) δ 1.43 (9H, s), 2.64-2.83 (2H, m), 3.98-4.42 (3H, m), 5.12(2H, d), 5.14 (2H, s), 6.97 (1H, d), 7.18 (1H, s), 7.28-7.40 (6H, m)

Step 2: Synthesis of(3R)-4-(5-amidino-2-hydroxyphenoxy)-3-[4-(1-acetimidoyl-4-piperidyloxy)benzoylamino]butanoicacid bistrifluoroacetate

2.0 g (3.88 mmol) of benzyl(3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-benzyloxyphenoxy)butanoate wasdissolved in 20 ml of 4 N solution of hydrogen chloride in dioxane, andthe obtained solution was stirred at room temperature for 4 hours. Thesolvent was evaporated and the obtained crude product was dissolved in20 ml of DMF. 1.36 g (4.26 mmol) of4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 980 mg (5.82 mmol) of2-chloro-1,3-dimethylimidazonium chloride and 1.6 ml (11.6 mmol) oftriethylamine were added to the obtained solution, and they were stirredfor 16 hours. After the treatment with ethyl acetate as the extractionsolvent in an ordinary manner, the obtained crude product was dissolvedin a mixture of 20 ml of 4 N solution of hydrogen chloride in dioxaneand 5 ml of ethanol, and they were stirred for 3 days. The solvent wasevaporated, and the obtained crude product was dissolved in 10 ml ofethanol. 500 mg of ammonium carbonate was added to the obtainedsolution, and they were stirred overnight. The solvent was evaporated,and the residue was dissolved in 20 ml of ethanol. 2.0 g of ethylacetimidate and 2 ml of triethylamine were added to the obtainedsolution, and they were stirred at room temperature overnight. Thesolvent was evaporated, and the obtained crude product was dissolved in10 ml of ethanol. 50 mg of 10% palladium/carbon was added to theobtained solution, and they were stirred in the presence of hydrogenovernight. The reaction liquid was filtered through Celite, and thesolvent was evaporated. The obtained crude product was dissolved in 10ml of 6 N aqueous hydrogen chloride solution, and the obtained solutionwas stirred at 6° C. for 2 hours. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 7.6 g (0.01 mmol) (0.3%)

MS (ESI,m/z) 498 (MH+)

H-NMR (DMSO) δ 1.62-1.85 (2H, m), 1.99-2.16 (2H, m), 2.27 (3H, s),2.62-2.88 (2H, m), 3.40-3.58 (2H, m), 3.63-3.81 (2H, m), 3.94-4.05 (1H,m), 4.60-4.82 (2H, m), 6.96 (1H, d), 7.06 (2H, d), 7.17-7.24 (1H, m),7.28-7.42 (1H, m), 7.79 (2H, d), 8.33 (1H, d), 8.60 (1H, br), 8.86 (2H,br), 9.01 (2H, br), 9.14 (1H, br)

EXAMPLE 29 Synthesis of(3R)-4-(5-amidino-2-hydroxyphenoxy)-3-[(1-(pyridine-4-yl)piperidine-4-carbonyl)amino]butanoicacid bistrifluoroacetate

Step 1: Synthesis of benzyl(3R)-4-(5-cyano-2-benzyloxyphenoxy)-3-[(1-(pyridine-4-yl)piperidine-4-carbonyl)amino]butanoate

2.1 g (4.07 mmol) of benzyl(3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-benzyloxyphenoxy)butanoate wasdissolved in 20 ml of 4 N solution of hydrogen chloride in dioxane, andthey were stirred at room temperature for 4 hours. The solvent wasevaporated and the obtained crude product was dissolved in 20 ml of DMF.1.08 g (1.03 mmol) of 1-(4-pyridyl)-4-piperidinecarboxylatehydrochloride, 1.03 g (6.11 mmol) of 2-chloro-1,3-dimethylimidazoniumchloride and 1.7 ml (61.6 mmol) of triethylamine were added to theobtained solution, and they were stirred for 16 hours. After thetreatment with ethyl acetate as the extraction solvent in an ordinarymanner, the obtained crude product was purified by the silica gel columnchromatography. 1.0 g (1.66 mmol) (of 2.0 g in total) of the obtainedproduct was dissolved in a mixture of 20 ml of 4 N solution of hydrogenchloride in dioxane and 4 ml of ethanol, and the obtained solution wasstirred at room temperature for 3 days. The solvent was evaporated underreduced pressure, and the obtained crude product was dissolved in 20 mlof ethanol. 1.0 g of ammonium carbonate was added to the obtainedsolution, and they were stirred at room temperature overnight. Thesolvent was evaporated, and the obtained crude product was dissolved in10 ml of ethanol. 100 mg of 10% palladium/carbon was added to theobtained solution, and they were stirred in the presence of hydrogenovernight. The reaction liquid was filtered through Celite, and thesolvent was evaporated. The obtained crude product was dissolved in 28ml of 6 N aqueous hydrogen chloride solution, and the obtained solutionwas stirred at 60° C. for 2 hours. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 350 mg (0.52 mmol) (26%)

MS (ESI, m/z) 442 (MH+)

H-NMR (DMSO) δ 1.42-1.64 (2H, m), 1.76-1.84 (2H, m), 2.44-2.81 (3H, m),3.17-3.28 (2H, m), 3.82-3.98 (1H, m), 4.02-4.22 (3H, m), 4.37-4.59 (1H,m), 6.98 (1H, d), 7.19 (2H, d), 7.38 (2H, d), 8.07 (1H, d), 8.22 (2H,d), 8.87 (2H, br), 9.03 (2H, br)

EXAMPLE 30 Synthesis of ethyl3-[4-N-hydroxyamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionatebistrifluoroacetate

225 mg (0.50 mmol) of ethyl3-[4-cyano-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionatewas dissolved in 2.5 ml of ethanol. 0.10 ml (0.75 mmol) of triethylamineand 52 mg (0.52 mmol) of hydroxylamine hydrochloride were added to theobtained solution, and they were stirred at 80° C. for 5 hours and thenat room temperature for 16 hours. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 170 mg (0.24 mmol) (50%)

MS (ESI, m/z) 484(MH+)

H-NMR (DMSO) δ 1.13 (2H, m), 1.44-1.66 (2H, m), 1.72-1.91 (2H, m),2.48-2.56 (1H, m), 2.57 (2H, t), 2.85 (2H, t), 3.06-3.30 (2H, m), 3.45(2H, dt), 4.01 (2H, q), 4.05 (2H, t), 4.11-4.25 (2H, m), 7.16 (2H, d),7.18 (2H, br), 7.32 (1H, d), 8.18 (1H, d), 8.19 (2H, d)

EXAMPLE 31 Synthesis of ethyl(2S)-3-[4-amidino-2-[4-ethoxycarbonyl-2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylatebistrifluoroacetate

Step 1: Synthesis of benzyl(4S)-4-t-butoxycarbonylamino-5-hydroxypentanoate

15 g (44.5 mmol) of γ-benzyl N-t-butoxycarbonyl-D-glutamate and 6.2 ml(44.5 mmol) of triethylamine were dissolved in 200 ml oftetrahydrofuran. 4.26 ml (44.5 mmol) of ethyl chloroformate was added tothe obtained solution under cooling with ice, and they were stirred for20 minutes. The precipitates thus formed were removed by the suctionfiltration. 5 g of ice and 1.69 g (44.5 mmol) of sodium borohydride wereadded to the filtrate under cooling with ice, and they were stirred for2 hours. 100 ml of 1 N aqueous hydrochloric acid solution was added tothe reaction mixture, and they were stirred at room temperature for onehour. After the treatment with ethyl acetate as the extraction solventin an ordinary manner, the obtained crude product was purified by thesilica gel column chromatography to obtain the title compound.

Yield: 9.2 g (28.5 mmol) (64%)

H-NMR (CDCl3) δ 1.44 (9H,s), 1.70-2.00 (2H,m), 2.28-2.58 (2H,m),3.50-3.72 (2H,m), 4.80 (1H, br), 5.13 (2H,s), 7.35 (5H,s).

Step 2: Synthesis of benzyl(4S)-4-t-butoxycarbonylamino-5-(5-cyano-2-iodophenoxy)pentanoate

7.5 g (23.2 mmol) of benzyl(4S)-4-t-butoxycarbonylamino-5-hydroxypentanoate, 8.53 g (34.8 mmol) ofiodocyanophenol and 9.13 g (34.8 mmol) of triphenylphosphine weredissolved in 120 ml of toluene. 5.99 g (34.8 mmol)) of diamide diazenedicarboxylic acid bis(N,N-dimethylamide) was added to the obtainedsolution under cooling with ice, and they were stirred at roomtemperature. The solvent was evaporated. After the treatment with ethylacetate as the extraction solvent in an ordinary manner, the obtainedcrude product was purified by the silica gel column chromatography toobtain the title compound.

Yield: 3.44 g (6.25 mmol) (27%)

H-NMR (CDCl3) δ 1.44 (9H,s), 2.00-2.20 (2H,m), 2.58 (2H,t), 4.05(2H,br), 4.85 (1H, br), 5.13 (2H,s), 6.90-7.10 (2H,m), 7.36 (5H,s), 7.87(1H,d).

Step 3: Synthesis of ethyl3-[(2S)-2-(2-t-butoxycarbonylamino-4-benzoxycarbonyl-butoxy)-4-cyanophenyl]acrylate

1.64 g (2.98 mmol) of benzyl(4S)-4-t-butoxycarbonylamino-5-(5-cyano-2-iodophenoxy)pentanoate wasdissolved in 30 ml of N,N-dimethylformamide (dehydrated). 0.65 ml (5.96mmol) of ethyl acrylate, 2.1 ml (14.9 mmol) of triethylamine and 14 mg(0.06 mmol) of palladium acetate were added to the obtained solution,and they were stirred at 100° C. overnight. After the treatment withethyl acetate as the extraction solvent in an ordinary manner, theobtained crude product was purified by the silica gel columnchromatography to obtain the title compound.

Yield: 1.42 g (2.71 mmol) (91%)

H-NMR (CDCl3) δ 1.31(3H,t), 1.43 (9H,s), 2.04 (2H,br), 2.54 (2H,t), 4.07(2H, br), 4.26 (2H,q), 5.13 (2H,s), 6.50 (1H,d), 7.18 (1H,s),7.27(1H,br), 7.35(5H,s), 7.57(1H,d), 7.97(1H,d).

Step 4: Synthesis of ethyl(2S)-3-[4-amidino-2-[4-ethoxycarbonyl-2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylatebistrifluoroacetate

1.42 g (2.71 mmol) of ethyl3-[(2S)-2-(2-t-butoxycarbonylamino-4-benzoxycarbonyl-butoxy)-4-cyanophenyl]acrylatewas dissolved in a mixture of 15 ml of dioxane and 15 ml of 4 N solutionof hydrogen chloride in dioxane, and the obtained solution was stirredat room temperature for 3 hours. The solvent was evaporated underreduced pressure, and the obtained crude product was dissolved in 10 mlof N,N-dimethylformamide. 0.72 g (2.98 mmol) of1-(4-pyridyl)piperidine-4-carboxylic acid hydrochloride and 0.55 g (3.25mmol) of 2-chloro-1,3-dimethylimidazolinium chloride were added to theobtained solution and then 2.3 ml (16.3 mmol) of triethylamine was addedto the obtained mixture under cooling with ice, and they were stirred atroom temperature overnight. The solvent was evaporated, and the residuewas dissolved in a mixture of 35 ml of 4 N solution of hydrogen chloridein dioxane and 3.5 ml of ethanol, and they were stirred at roomtemperature for 3 days. The solvent was evaporated, and the residue wasdissolved in 50 ml of ethanol. 1.6 g (28.7 mmol) of ammonium carbonatewas added to the obtained solution, and they were stirred at roomtemperature overnight. The solvent was evaporated, and the obtainedcrude product was treated in the same manner as that in step 9 inExample 1 to obtain the title compound.

Yield: 387.6 mg (0.488 mmol) (36%)

MS (ESI, m/z) 566 (MH+)

H-NMR (DMSO-d6) δ 1.17 (3H,t), 1.23 (3H,t), 1.50-2.00 (4H,m), 2.30-2.65(4H,m), 3.22 (2H,br), 4.00-4.30 (8H, m), 6.78 (1H,d), 7.18 (2H,d), 7.44(1H, d), 7,52 (1H, s), 7.86 (1H, d), 7.98 (1H, d), 8.22 (2H, d), 9.13(1H,br), 9.32 (1H,br), 9.35(1H,br).

EXAMPLE 32 Synthesis of(2S)-3-[4-amidino-2-[4-carbonyl-2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylicacid bistrifluoroacetate

2.5 g of crude ethyl(2S)-3-[4-amidino-2-[4-ethoxycarbonyl-2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylatebistrifluoroacetate was dissolved in 25 ml of 6 N aqueous hydrochloricacid solution, and the obtained solution was stirred at 80° C. for 3hours. The solvent was evaporated, and the obtained crude product wastreated in the same manner as that in step 9 in Example 1 to obtain thetitle compound.

Yield: 131.54 mg (0.18 mmol) (14%)

MS (ESI, m/z) 510(MH+)

H-NMR (DMSO-d6) δ 1.52-1.96 (4H,m), 2.30 (2H,br), 2.60(2H,br),3.22(2H,br), 4.00-4.28(4H,m), 6.68(1H,d), 7.18(2H,d), 7.44(1H,d),7.52(1H,s), 7.81(1H,d), 7.94(1H,d), 8.02(1H,d), 8.22(2H,d), 9.22(1H,br),9.28(1H,br), 9.34(1H,br).

EXAMPLE 33 Synthesis of(4S)-5-[5-amidino-2-[4-carboxy-ethyl]phenoxy]-4-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]pentanoic acid bistrifluoroacetate

365 mg (0.46 mmol) of(2S)-3-[4-amidino-2-[4-carbonyl-2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]butoxy]phenyl]acrylatebistrifluoroacetate was dissolved in a mixture of 10 ml of ethanol and0.1 ml of N,N-dimethylformamide. 15 mg of 10% palladium/carbon (50%hydrous) was added to the obtained solution, and they were stirred inthe presence of hydrogen overnight. The solvent was evaporated, and theobtained product was filtered through Celite and then treated in thesame manner as that in step 9 in Example 1 to obtain the title compound.

Yield: 34.2 mg (0.046 mmol) (10%)

MS (ESI, m/z) 612 (MH+)

H-NMR (DMSO-d6) δ 1.50-2.00(4H,m), 2.30(2H,br), 2.50-2.70(2H,m),2.85(2H,br), 3.20(2H,br), 3.95-4.30(6H, m), 7.20(2H,d), 7.38(3H,m),8.00(1H,d), 8.30(2H,d), 9.14(2H,m), 9.23(1H,br).

EXAMPLE 34 Synthesis of methyl4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]benzoatebistrifluoroacetate

Step 1: Synthesis of methyl2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanobenzoate

5 g (12.88 mmol) of3-(2-(t-butoxycarbonylamino)ethoxy)-4-iodobenzonitrile was dissolved in60 ml of N,N-dimethylformamide (dehydrated). 3.6 ml (25.8 mmol) oftriethylamine, 10 ml (25.8 mmol) of methanol and 145 mg (0.644 mmol) ofpalladium acetate were added to the obtained solution, and they werestirred in the presence of carbon monoxide at 90° C. for 6 hours. Thesolvent was evaporated. After the treatment with ethyl acetate as theextraction solvent in an ordinary manner, the obtained crude product waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 4.11 g (12.82 mmol) (99.5%)

H-NMR (CDCl3) δ 1.44(9H,s), 3.61(2H,q), 3.94(3H,s), 4.12(2H,m),5.38(1H,br), 7.21(1H, s), 7.38(1H,m), 7.87(1H,d).

Step 2: Synthesis of methyl4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]benzoatebistrifluoroacetate

1.5 g (4.68 mmol) of methyl2-(2-(t-butoxycarbonylamino)ethoxy-4-cyanobenzoate was dissolved in amixture of 15 ml of dioxane and 15 ml of 4 N solution of hydrogenchloride in dioxane, and the obtained solution was stirred at roomtemperature for 3 hours. The obtained crude product was dissolved in 6ml of N,N-dimethylformamide (dehydrated). 0.32 g (1.29 mmol) of1-(4-pyridyl)piperidine-4-carboxylic acid hydrochloride and 0.24 g (1.40mmol) of 2-chloro-1,3-dimethylimidazolinium chloride were added to theobtained solution and then 1 ml (7.02 mmol) of triethylamine was addedto the obtained mixture under cooling with ice, and they were stirred atroom temperature overnight. After the treatment with chloroform as theextraction solvent in an ordinary manner, the obtained crude product wasdissolved in a mixture of 2 ml of 4 N solution of hydrogen chloride indioxane and 0.2 ml of ethanol, and they were stirred at room temperaturefor 3 days. The solvent was evaporated, and the residue was dissolved in50 ml of ethanol. 0.14 g (2.45 mmol) of ammonium carbonate was added tothe obtained solution, and they were stirred at room temperatureovernight. The solvent was evaporated, and the obtained crude productwas treated in the same manner as that in step 9 in Example 1 to obtainthe title compound.

Yield: 92 mg (0.14 mmol) (12%)

MS (ESI, m/z) 426(MH+)

H-NMR (DMSO-d6) δ 1.50-1.90(4H,m), 2.60(2H,m), 3.23(2H,m), 3.45(2H,q),3.85(3H,s), 4.18(3H,m), 7.20(2H,d), 7.44(1H,d), 7.53(1H,s), 7.80(1H,d),8.09(1H,t), 8.22(2H,d), 9.40(2H,m), 9.43(1H,br).

EXAMPLE 35 Synthesis of ethyl4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]benzoatebistrifluoroacetate

The title compound was obtained as a by-product in step 2 in Example 34.

Yield: 26 mg (0.039 mmol) (3%)

MS (ESI, m/z) 440(MH+)

H-NMR (DMSO-d6) δ 1.30(3H,t), 1.50-1.90(4H,m), 2.53-2.65(2H,m),3.23(2H,t), 3.48(2H,q), 4.10-4.35(4H,m), 7.20(2H,d), 7.45(1H,d),7.53(1H,s), 7.79(1H,d), 8.10(1H,t), 8.23(2H,d), 9.40(2H,br),9.43(1H,br).

EXAMPLE 36 Synthesis of4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]benzoicacid bistrifluoroacetate

50 mg (0.077 mmol) of methyl4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]benzoatebistrifluoroacetate obtained in Step 2 in Example 34 was dissolved in 1ml of 6 N aqueous hydrochloric acid solution, and the obtained solutionwas stirred at 90° C. for 3 hours. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 45.3 mg (0.071 mmol) (92%)

MS (ESI, m/z) 412 (MH+)

H-NMR (DMSO-d6) δ 1.50-1.67 (2H,m), 1.79-2.02 (2H,m), 2.53-2.74 (2H,m),3.16-3.37 (2H,m), 3.47 (2H,q), 4.06-4,26 (3H,m), 7.20 (2H,d), 7.44(1H,d), 7.53 (1H,br), 7.77 (1H,d), 8.09 (1H,t), 8.22 (2H,d), 9.42(1H,br), 9.53 (2H,br).

EXAMPLE 37 Synthesis ofN-[2-(5-amidino-2-hydroxymethylphenoxy)ethyl]-1-(1-(1-pyridine-4-yl)piperidine)carboxamidebistrifluoroacetate

Step 1: Synthesis of3-(2-(t-butoxycarbonylamino)ethoxy)-4-hydroxymethylbenzonitrile

4.15 g (12.95 mmol) of methyl2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanobenzoate obtained in the samemanner as that in step 1 in Example 34 was dissolved in 60 ml oftetrahydrofuran (dehydrated). 3.2 ml (129.5 mmol) of 2 M Lithiumborohydride was added to the obtained solution under cooling with ice,and they were stirred at room temperature overnight.

The solvent was evaporated. After the treatment with ethyl acetate asthe extraction solvent in an ordinary manner, the obtained crude productwas purified by the silica gel column chromatography to obtain the titlecompound.

Yield: 2.38 g (8.12 mmol) (63%)

H-NMR (CDCl3) δ 1.41 (9H,s), 3.00 (1H,br), 3.60 (2H,br), 4.10 (2H,t),4.70 (2H,d), 4.95 (1H,br), 7.07 (1H,s), 7.30 (1H,d), 7.41 (1H,d).

Step 2: Synthesis ofN-[2-(5-amidino-2-hydroxymethylphenoxy)ethyl]-1-(1-(1-pyridine-4-yl)piperidine)carboxamidebistrifluoroacetate

2.38 g (8.12 mmol) of3-(2-(t-butoxycarbonylamino)ethoxy)-4-hydroxymethylbenzonitrile wasdissolved in a mixture of 20 ml of dioxane and 20 ml of 4 N solution ofhydrogen chloride in dioxane, and the obtained solution was stirred atroom temperature for 3 hours. The obtained crude product was dissolvedin 10 ml of N,N-dimethylformamide (dehydrated). 1.25 g (5.1 mmol) of1-(4-pyridyl)piperidine-4-carboxylic acid hydrochloride, 0.95 g (5.6mmol) of 2-chloro-1,3-dimethylimidazolinium chloride and 4 ml (27.8mmol) of triethylamine were added to the obtained solution, and then andthey were stirred at room temperature overnight. After the treatmentwith dichloromethane as the extraction solvent in an ordinary manner,the obtained crude product was dissolved in a mixture of 20 ml of 4 Nsolution of hydrogen chloride in dioxane and 2 ml of ethanol, and theywere stirred at room temperature for 3 days. The solvent was evaporated,and the residue was dissolved in 50 ml of ethanol. 1.3 g (23.15 mmol) ofammonium carbonate was added to the obtained solution, and they werestirred at room temperature overnight. The solvent was evaporated, andthe obtained crude product was treated in the same manner as that instep 9 in Example 1 to obtain the title compound.

Yield: 275 mg (0.44 mmol) (11%)

MS (ESI, m/z) 398(MH+)

H-NMR (DMSO-d6) δ 1.50 (2H,br), 1.80 (2H,br), 2.60 (2H,br), 3.20(2H,br), 3.47 (2H,m), 4.18-4.24 (3H,m), 4.58 (2H,s), 7.19 (2H,d), 7.35(1H,s), 7.45(1H,d), 7.60(1H,d), 8.21(2H,d), 9.25(3H,m).

EXAMPLE 38 Synthesis of methyl4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-piperidyloxy]benzoylamino)ethoxy]benzoatebistrifluoroacetate

Step 1: Synthesis of methyl4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-piperidyloxy]benzoylamino)ethoxy]benzoatebistrifluoroacetate

0.586 g (2.35 mmol) of methyl 3-(2-aminoethoxy)-4-cyanobenzoatehydrochloride was dissolved in 10 ml of N,N-dimethylformamide(dehydrated). 0.82 g (2.56 mmol) of4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid and 0.48 g (2.82 mmol)of 2-chloro-1,3-dimethylimidazolinium chloride were added to theobtained solution, and then 2 ml (14.1 mmol) of triethylamine was addedto the obtained mixture under cooling with ice. They were stirred atroom temperature overnight. The solvent was evaporated, and the obtainedcrude product was dissolved in a mixture of 10 ml of dioxane and 10 mlof 4 N solution of hydrogen chloride in dioxane, and the obtainedsolution was stirred at room temperature for 4 hours. The solvent wasevaporated, and the residue was dissolved in 12 ml of ethanol. 0.87 g(7.05 mmol) of ethyl acetimidate hydrochloride and 1.64 ml (11.75 mmol)of triethylamine were added to the obtained solution, and they werestirred at room temperature overnight. The solvent was evaporated, andthe residue was dissolved in a mixture of 20 ml of 4 N solution ofhydrogen chloride in dioxane and 3 ml of ethanol, and the obtainedsolution was stirred at room temperature for 3 days. The solvent wasevaporated, and the obtained crude product was dissolved in 10 ml ofethanol. 0.67 g (11.75 mmol) of ammonium carbonate was added to theobtained solution, and they were stirred at room temperature overnight.The solvent was evaporated, and the obtained crude product was treatedin the same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 484.5 mg (0.68 mmol) (29%)

MS (ESI, m/z) 480(MH−)

H-NMR (DMSO-d6) δ 1.77(2H,br), 2.08(2H,br), 2.50(3H,s), 3.48-3.70(6H,m),3.79(3H,s), 4.28(2H,br), 4.80(1H,br), 7.07(2H,d), 7.44(1H,d),7.58(1H,s), 7.75-7.89(3H,m), 8.52(1H,br), 8.62(1H,br), 9.17(1H,br), 9.37(1H,br), 9.42 (1H,br).

EXAMPLE 39 Synthesis of ethyl4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-piperidyloxy]benzoylamino)ethoxy]benzoatebistrifluoroacetate

The title compound was obtained as a by-product in step 2 in Example 38.

Yield: 165.6 mg (0.23 mmol) (10%)

MS (ESI, m/z) 494(MH−)

H-NMR (DMSO-d6) δ 1.25 (3H,t), 1.77(2H,br), 2.08(2H,br), 2.29(3H,s),3.48-3.85(6H,m), 4.20-4.35 (4H,m), 4.80 (1H,br), 7.07(2H,d), 7.44(1H,d), 7.58(1H,br), 7.77(1H,br), 7.84 (2H,d), 8.52(1H,br), 8.63(1H,br),9.17(1H,br), 9.37 (1H,br), 9.42 (1H,br).

EXAMPLE 40 Synthesis of4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-piperidyloxy]benzoylamino)ethoxy]benzoicacid bistrifluoroacetate

0.3 g (0.423 mmol) of ethyl4-amidino-2-[2-(4-[1-(1-acetimidoyl)-4-piperidyloxy]benzoylamino)ethoxy]benzoatebistrifluoroacetate obtained in Example 39 was dissolved in 10 ml ofconcentrated hydrochloric acid solution, and the obtained solution wasstirred at 80° C. for 3 hours. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 231.6 mg (0.333 mmol) (79%)

MS (ESI, m/z) 468 (MH+)

H-NMR (DMSO-d6) δ 1.77(2H,br), 2.08(2H,br), 2.29(3H,s), 3.48-3.85(6H,m),4.28(2H,t), 4.80(1H,br), 7.07(2H,d), 7.42(1H,d), 7.58(1H,br),7.78(1H,d), 7.84(2H,d), 8.50(1H,t), 8.63(1H,br), 9.17 (1H,br),9.38(2H,br).

EXAMPLE 41 Synthesis of2-[4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl]vinylsulfonicacid bistrifluoroacetate

Step 1: Synthesis of3-(2-(t-butoxycarbonylamino)ethoxy)-4-formylbenzonitrile

0.3 g (1.03 mmol) of3-(2-(t-butoxycarbonylamino)ethoxy)-4-hydroxymethylbenzonitrile obtainedin the same manner as that in step 1 in Example 37 was dissolved in 3 mlof dichloromethane (dehydrated). 0.36 g (4.1 mmol) of activatedmanganese dioxide was added to the obtained solution in the presence ofargon at room temperature, and they were stirred overnight. The reactionliquid was filtered through Celite to obtain the title compound.

Yield: 279 mg (0.962 mmol) (93%)

MS (ESI, m/z) 291 (MH−)

H-NMR (CDCl3) δ 1.53 (9H,s), 3.62 (2H,q), 4.20 (2H,t), 4.95 (1H, br),7.35(2H,m), 7.93 (1H,d), 10.50 (1H,s).

Step 2: Synthesis of ethyl3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]ethylenesulfonate

280 mg (1.15 mmol) of diethylphosphorylmethane sulfonate was dissolvedin 5 ml of triethylamine (dehydrated). 0.75 ml (1.15 mmol) of 1.54 Msolution of n-butyllithium in hexane was added to the obtained solutionin the presence of argon at −78°C., and they were stirred for 20minutes. 279 mg (0.962 mmol) of3-(2-(t-butoxycarbonylamino)ethoxy)-4-formylbenzonitrile was added tothe obtained mixture, and they were stirred at −78° C. for 45 minutesand then at room temperature for 3 hours. The solvent was evaporated.After the treatment with dichloromethane as the extraction solvent in anordinary manner, the obtained crude product was purified by the silicagel column chromatography to obtain the title compound.

Yield: 197 mg (0.498 mmol) (52%)

MS (ESI, m/z) 367 (MH−)

H-NMR (CDCl3) δ 1.35-1.50 (12H,m), 3.58 (2H,br), 4.10-4.30 (4H,m), 5.00(1H,br), 7.00 (1H,d), 7.20 (1H,s), 7.28 (1H,d), 7.63 (1H,d), 7.63(1H,d), 7.78(1H,d).

Step 3: Synthesis of2-[4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl]vinylsulfonicacid bistrifluoroacetate

197 mg (0.498 mmol) of ethyl3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl)ethylenesulfonatewas dissolved in a mixture of 2 ml of dioxane and 2 ml of 4 N solutionof hydrogen chloride in dioxane, and the obtained solution was stirredat room temperature for 3 hours. The solvent was evaporated, and theobtained crude product was dissolved in 3 ml of N,N-dimethylformamide(dehydrated). 134 mg (0.548 mmol) of1-(4-pyridyl)-piperidine-4-carboxylic acid hydrochloride, 101 mg (0.598mmol) of 2-chloro-1,3-dimethylimidazolium chloride and 0.4 ml (3 mmol)of triethylamine were added to the obtained solution, and they werestirred at room temperature for 3 hours. The solvent was evaporated, andthe residue was dissolved in a mixture of 2 ml of ethanol and 20 ml of 4N solution of hydrogen chloride in dioxane, and the obtained solutionwas stirred at room temperature for 3 days. The solvent was evaporated,and the residue was dissolved in 20 ml of ethanol. 0.41 g (2.5 mmol) ofammonium carbonate was added to the obtained solution, and they werestirred at room temperature overnight. The solvent was evaporated, andthe obtained crude product was treated in the same manner as that instep 9 in Example 1 to obtain the title compound.

Yield: 120.8 mg (0.172 mmol) (35%)

MS (ESI, m/z) 476(MH+)

H-NMR (DMSO-d6) δ 1.48-1.70 (2H,m), 1.80-2.00 (2H,m), 2.55-3.05 (3H,m),3.22 (2H,t), 3.50 (2H,br), 4.22 (2H,br), 7.03-7.08 (1H,d), 7.18-7.50(5H,m), 7.80 (1H,d), 8.19 (2H,d),9.05 (2H,s), 9.30 (2H,s).

Example 42 Synthesis of2-[4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl]ethanesulfonic acid bistrifluoroacetate

72.2 mg (0.103 mmol) of2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinylsulfonic acid bistrifluoroacetate obtained instep 3 in Example 41 was dissolved in 20 ml of ethanol. 30 mg of 10%palladium/carbon (50% hydrous) was added to the obtained solution in thepresence of argon, and they were stirred at room temperature in thepresence of hydrogen overnight. After the filtration through Celite, theobtained crude product was treated in the same manner as that in step 9in Example 1 to obtain the title compound.

Yield: 10.5 mg (0.015 mmol) (15%)

MS (ESI, m/z) 474 (MH+)

H-NMR (DMSO-d6) δ 1.48-1.65(2H,m), 1.80-1.95 (2H,m), 2.60-3.05(5H,m),3.20 (2H,br), 3.53 (2H,br), 4.08 (2H,br), 4.20 (2H,d), 7.14-7.25 (3H,m),7.34 (1H,s), 7.41 (1H,d), 8.20 (2H,d), 8.48 (1H,br), 8.98 (2H,br), 9.22(2H,br).

EXAMPLE 43 Synthesis ofN-[2-(5-amidino-2-hydroxypropylphenoxy)ethyl]-1-(1-(1-pyridine-4-yl)piperidine)carboxamidebistrifluoroacetate

Step 1: Synthesis of3-(2-(t-butoxycarbonylamino)ethoxy)-4-(3-hydroxypropyl)benzonitrile

1.1 g (3.04 mmol) of ethyl3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]propionate wasdissolved in 15 ml of tetrahydrofuran (dehydrated). 1.5 ml (2.3 mmol) of2 M Lithium borohydride was added to the obtained solution under coolingwith ice, and they were stirred at room temperature overnight. Thesolvent was evaporated. After the treatment with ethyl acetate as theextraction solvent in an ordinary manner, the obtained crude product waspurified by the silica gel column chromatography to obtain the titlecompound.

Yield: 524 mg (1.64 mmol) (54%)

H-NMR (CDCl3) δ 1.45 (9H,s), 1.80 (2H,br), 2.80 (2H,t), 3.54-3.69(4H,m), 4.02 (2H,t), 5.30 (1H,br), 7.03 (1H,s), 7.23-7.26 (2H,m).

Step 2: Synthesis ofN-[2-(5-amidino-2-hydroxypropylphenoxy)ethyl]-1-(1-(1-pyridine-4-yl)piperidine)carboxamidebistrifluoroacetate:

524 mg (1.64 mmol) of3-(2-(t-butoxycarbonylamino)ethoxy)-4-(3-hydroxypropyl)benzonitrile wasdissolved in a mixture of 4 ml of dioxane and 4 ml of 4 N solution ofhydrogen chloride in dioxane, and the obtained solution was stirred atroom temperature for 2 hours. The solvent was evaporated and theobtained crude product was dissolved in 5 ml of N,N-dimethylformamide(dehydrated). 440 mg (1.80 mmol) of 1-(4-pyridyl)piperidine-4-carboxylicacid hydrochloride, 330 mg (1.97 mmol) of2-chloro-1,3-dimethylimidazolinium chloride and 1.4 ml (9.84 mmol) oftriethylamine were added to the obtained solution, and they were stirredat room temperature overnight. The solvent was evaporated, and theobtained crude product was treated with dichloromethane as theextraction solvent in an ordinary manner, and the obtained crude productwas dissolved in a mixture of 10 ml of 4 N solution of hydrogen chloridein dioxane and 1 ml of ethanol, and they were stirred at roomtemperature for 3 days. The solvent was evaporated, and the residue wasdissolved in 10 ml of ethanol. 0.46 g (8.2 mmol) of ammonium carbonatewas added to the obtained solution, and they were stirred at roomtemperature overnight. The solvent was evaporated, and the obtainedcrude product was treated in the same manner as that in step 9 inExample 1 to obtain the title compound.

Yield: 178.5 mg (0.273 mmol) (17%)

MS (ESI, m/z) 426 (MH+)

H-NMR (DMSO-d6) δ 1.49-1.95 (6H,m), 2.55-2.75 (4H,m), 3.25 (2H,t), 3.50(4H,br), 4.09 (2H,t), 4.20 (1H,br), 7.18 (1H,s), 7.35 (1H,d),8.22(1H,d),9.19 (2H,br), 9.23 (2H,br).

EXAMPLE 44 Synthesis of diethyl2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinylphosphatebistrifluoroacetate

Step 1: Synthesis of diethyl2-[(2-(2-t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]vinylphosphate

0.54 ml (2.18 mmol) of tetraethylmethylene diphosphonate was dissolvedin 10 ml of tetrahydrofuran (dehydrated). 1.5 ml (2.31 mmol) of 1.54 Msolution of n-butyllithium in hexane was added to the obtained solutionin the presence of argon at −78° C., and they were stirred for 20minutes. 527 mg (1.82 mmol) of3-(2-(t-butoxycarbonylamino)ethoxy)-4-formylbenzonitrile obtained in thesame manner as that in step 1 in Example 41 was added to the obtainedmixture, and they were stirred at −78° C. for 45 minutes and then atroom temperature for 3 hours. The solvent was evaporated. After thetreatment with dichloromethane as the extraction solvent in an ordinarymanner, the obtained crude product was purified by the silica gel columnchromatography to obtain the title compound.

Yield: 0.45 g (1.06 mmol) (58%)

H-NMR (CDCl3) δ 1.17-1.42 (6H,m), 1.47 (9H,s), 3.60 (2H,br), 3.96-4.23(6H,m), 5.00 (1H,br), 6.40 (2H,m), 7.15 (1H,s), 7.27 (1H,d), 7.58(1H,d). Step 2: Synthesis of diethyl[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinylphosphatebistrifluoroacetate

0.45 g (1.06 mmol) of diethyl[2-[(2-(2-t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]vinyl]phosphatewas dissolved in a mixture of 5 ml of dioxane and 5 ml of 4 N solutionof hydrogen chloride in dioxane, and the obtained solution was stirredat room temperature for 3 hours. The solvent was evaporated, and theobtained crude product was dissolved in 10 ml of N,N-dimethylformamide(dehydrated). 0.29 g (1.2 mmol) of 1-(4-pyridyl)-4-piperidinecarboxylicacid hydrochloride, 0.5 g (2.8 mmol) of 2-chloro-1,3-dimethylimidazoniumchloride and 1.8 ml (12.8 mmol) of triethylamine were added to theobtained solution, and they were stirred overnight. After the treatmentwith dichloromethane as the extraction solvent in an ordinary manner,the obtained crude product was dissolved in a mixture of 5 ml of 4 Nhydrogen chloride in dioxane and 0.5 ml of ethanol, and the obtainedsolution was stirred at room temperature for 3 days. The solvent wasevaporated, and the residue was dissolved in 5 ml of ethanol. 0.19 g(3.35 mmol) of ammonium carbonate was added to the obtained solution,and they were stirred at room temperature overnight. The solvent wasevaporated, and the obtained crude product was treated in the samemanner as that in step 9 in Example 1 to obtain the title compound.

Yield: 155 mg (0.204 mmol) (31%)

MS (ESI, m/z) 530 (MH+)

H-NMR (DMSO-d6) δ 1.26 (6H,t), 1.50-1.92 (4H,m), 2.58 (2H,br), 3.22(2H,t), 3.50 (2H,br), 4.03 (4H,m), 4.20 (3H,br), 6.77 (2H,m), 7.19(2H,d), 7.40-7.74 (3H,m),7.96 (1H,d), 8.21 (2H,d),9.33(2H,br),9.36(2H,br).

EXAMPLE 45 Synthesis of monoethyl[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinyl]phosphatebistrifluoroacetate

This compound was a by-product obtained in step 2 in Example 44.

Yield: 63.4 mg (0.087 mmol) (13%)

MS (ESI, m/z) 502 (MH+)

H-NMR (DMSO-d6) δ 1.23 (3H,t), 1.50-1.95 (4H,m), 2.58 (2H,br), 3.22(2H,t), 3.50 (2H,br), 3.95 (2H,m), 4.22 (3H,br), 6.71 (2H,m), 7.18(2H,d), 7.38-7.66 (3H,m),7.92 (1H,d), 8.20 (2H,d),9.21(2H,br),9.34(2H,br).

Example 46 Synthesis of monoethyl[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)ethyl]phosphatebistrifluoroacetate

63.4 mg (0.087 mmol) of monoethyl[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinyl]phosphatebistrifluoroacetate was dissolved in 2 ml of ethanol. 10 mg of 10%palladium/carbon (50% hydrous) was added to the obtained solution in thepresence of argon, and they were stirred in the presence of hydrogen atroom temperature overnight. 2 ml of water was added to the reactionmixture. The solvent was evaporated, and the obtained crude product wastreated in the same manner as that in step 9 in Example 1 to obtain thetitle compound.

Yield: 43.1 mg (0.059 mmol) (68%)

MS (ESI, m/z) 504 (MH+)

H-NMR (DMSO-d6) δ 1.20 (3H,t), 1.58 (2H,br), 1.80-1.96 (4H,m), 2.62(2H,br), 2.80 (2H,br), 3.21 (2H,t), 3.49 (2H,q), 3.88-3.98 (2H,m), 4.12(2H,t) 4.20 (1H,br), 7.18 (2H,d), 7.37-7.42 (3H,m), 8.21 (2H,d), 8.28(1H,br),9.18(2H,br), 9.25(2H,br).

EXAMPLE 47 Synthesis of diethyl[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)ethyl]phosphatebistrifluoroacetate

155 mg (0.204 mmol) of diethyl[2-(4-amidino-2-[2-[(1-(1-pyridine-4-yl)piperidine-4-carbonyl)amino]ethoxy]phenyl)vinyl]phosphatebistrifluoroacetate was dissolved in 2 ml of ethanol. 20 mg of 10%palladium/carbon (50% hydrous) was added to the obtained solution in thepresence of argon, and they were stirred in the presence of hydrogen atroom temperature overnight. 2 ml of water was added to the reactionmixture. The solvent was evaporated, and the obtained crude product wastreated in the same manner as that in step 9 in Example 1 to obtain thetitle compound.

Yield: 26.75 mg (0.0352 mmol) (17%)

MS (ESI, m/z) 532 (MH+)

H-NMR (DMSO-d6) δ 1.19 (6H,t), 1.59 (2H,br), 1.80(2H,br), 2.01 (2H,br),2.58 (2H,br), 2.82 (2H,br), 3.19 (2H,t), 3.47 (2H,br), 3.91-4.00 (4H,m),4.09-4.21(3H,m), 7.17 (2H,d), 7.36-7.41 (3H,m),8.19 (3H,br),9.25(2H,br), 9.27(2H,br).

EXAMPLE 48 Synthesis of3-[4-N-ethoxycarbonylamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

200 mg (0.299 mmol) of3-[4-amidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate was dissolved in 5 ml of DMF. 0.124 ml (0.897mmol) of triethylamine and 0.028 ml (0.299 mmol) of ethyl chloroformatewere added to the obtained solution, and they were stirred at roomtemperature overnight. The solvent was evaporated, and the obtainedcrude product was treated in the same manner as that in step 9 inExample 1 to obtain the title compound.

Yield: 36 mg (0.049 mmol) (16%)

MS (ESI, m/z) 512 (MH+)

H-NMR (DMSO) δ 1.24 (3H, t), 1.44-1.62 (2H, m), 1.76-1.91 (2H, m), 2.32(2H, t), 2.48-2.53 (1H, m), 2.81 (2H, t), 3.10-3.23 (2H, m), 3.46 (2H,dt), 4.08 (2H, t), 4.18 (2H, q), 4.19-4.23 (2H, m), 6.77 (1H, br), 7.17(2H, d), 7.25 (1H, br), 7.42 (2H, d ), 8.15 (1H, d), 8.20 (2H, d)

EXAMPLE 49 Synthesis of3-[4-N-hydroxyamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

50 mg (0.070 mmol) of ethyl3-[4-N-hydroxyamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionatebistrifluoroacetate was dissolved in 10 ml of 6 N aqueous hydrochloricacid solution, and the obtained solution was stirred at 60° C. for 2hours.

The solvent was evaporated, and the obtained crude product was treatedin the same manner as that in step 9 in Example 1 to obtain the titlecompound.

Yield: 24 mg (0.035 mmol) (50%)

MS (ESI, m/z) 455 (MH+)

H-NMR (DMSO) δ 1.44-1.65 (2H, m), 1.74-1.88 (2H, m), 2.48-2.56 (1H, m),2.53 (2H,t), 2.84 (2H, t), 3.11-3.24 (2H, m), 3.45 (2H, dt), 4.08 (2H,t), 4.11-4.23 (2H, m), 7.16 (2H, d), 7.24 (2H, br), 7.34 (1H, d), 8.17(1H, d ), 8.18 (2H, d), 8.92 (2H, br)

Example 50 Synthesis of3-[4-N-acetoxyamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate

24 mg (0.035 mmol) of3-[4-N-hydroxyamidino-2-(2-((1-(pyridine-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]propionicacid bistrifluoroacetate was dissolved in a mixture of 5 ml of aceticacid and 0.08 ml of acetic anhydride, and the obtained solution wasstirred at room temperature for 3 hours. The solvent was evaporated, andthe obtained crude product was treated in the same manner as that instep 9 in Example 1 to obtain the title compound.

Yield: 2.6 mg (0.0035 mmol) (10%)

MS (ESI, m/z) 498 (MH+)

H-NMR (DMSO) δ 1.44-1.63 (2H, m), 1.78-1.90 (2H, m), 2.11 (3H, s),2.48-2.56 (1H, m), 2.53 (2H, t), 2.80 (2H, t), 3.08-3.23 (2H, m), 3.45(2H, t) 4.04 (2H, t), 4.13-4.25 (2H, m), 6.74 (2H, br), 7.16-7.23 (5H,m), 8.11 (1H, t), 8.18 (2H, d)

EXAMPLE 51 Synthesis of3-[4-amidino-2-]2-(4-(1-methyl-2-imidazoline-2-yl)benzoylamino)ethoxy)phenyl]-2-oxopropionicacid bistrifluoroacetate

Step 1: Synthesis of 4-(1-methyl-2-imidazoline-2-yl)benzoic acidmonohydrochloride

1.8 g (10.3 mmol) of ethyl 4-cyanobenzoate was dissolved in a mixture of20 ml of 4 N solution of hydrogen chloride in dioxane and 5 ml ofethanol, and the obtained solution was stirred at room temperature for 3days. The solvent was evaporated, and the residue was washed with ethylacetate. The obtained crude product was dissolved in 20 ml of ethanol.1.52 g (20.6 mmol) of N-methylethylenediamine was added to the obtainedsolution, and they were heated under reflux for 6 hours. The solvent wasevaporated, and the obtained crude product was treated withdichloromethane as the extraction solvent in an ordinary manner. Theobtained crude product was dissolved in 10 ml of concentratedhydrochloric acid, and the obtained solution was stirred at 50° C.overnight. The solvent was evaporated to obtain the crude titlecompound.

Yield: 1.37 g (5.71 mmol) (55%)

Step 2: Synthesis of 3-hydroxy-4-iodobenzoic acid

30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml ofacetic acid. 53.0 g (326 mmol) of iodine monochloride was added to theobtained solution at room temperature. After stirring at 45° C. for 15hours, the solvent was evaporated under reduced pressure, and theobtained residue was washed with 500 ml of 1% aqueous sodium thiosulfatesolution twice and then with 500 ml of water twice, and dried to solidat 80° C. under reduced pressure to obtain the title compound.

Yield: 17.2 g (65.2 mmol) (30%)

MS (FAB, m/z) 265 (MH+)

H-NMR (DMSO-d6) δ: 7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)

Step 3 Synthesis of 3-hydroxy-4-iodobenzonitrile

22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid was dissolved in 300ml of tetrahydrofuran. 19.7 ml (206 mmol) of ethyl chloroformate and28.7 ml (206 mmol) of triethylamine were added to the obtained solutionat 0° C. After stirring for 15 minutes, triethylamine hydrochloride thusformed was filtered out. The filtrate was added to 300 ml of atetrahydrofuran solution, obtained by bubbling with ammonia, at 0° C.After stirring at room temperature for 10 hours, the solvent wasevaporated under reduced pressure, and the residue was dissolved in 450ml of dioxane. 17.4 ml (117 mmol) of anhydrous trifluoroacetic acid and21.8 ml (269 mmol) of pyridine were added to the obtained solution at 0°C. After stirring at room temperature for 18 hours, the solvent wasevaporated under reduced pressure, and the residue was treated withchloroform as the extraction solvent in an ordinary manner to obtain anoily residue. The residue was dissolved in 180 ml oftetrahydrofuran/methanol (1:1). 90 ml (90.0 mmol) of 1 N aqueous sodiumhydroxide solution was added to the obtained solution at roomtemperature. After stirring them for 4 hours, the solvent was evaporatedunder reduced pressure, and the obtained residue was washed withdichloromethane. The reaction mixture was acidified with 1 N hydrogenchloride and then treated with ethyl acetate as the extraction solventin an ordinary manner to obtain the crude product, which was purified bythe silica gel column chromatography to obtain the title compound.

Yield: 9.29 g (37.9 mmol) (42%)

MS (FAB, m/z) 246 (MH+)

H-NMR (CDCl3) δ:5.63 (1H, br), 6.96 (1H, dd), 7.23 (1H, d), 7.79 (1H, d)

Step 4: Synthesis of t-butyl (2-bromoethyl)carbamate

9.22 g (45 mmol) of 2-bromoethylamine hydrobromide was dissolved in 100ml of dichloromethane. 7.64 g (35 mmol) of di-t-butyl dicarbonate, 10.0g (99 mmol) of triethylamine and 100 mg (0.82 mmol) of4-(dimethylamino)pyridine were added to the obtained solution, and theywere stirred overnight. After the treatment with dichloromethane as theextraction solvent in an ordinary manner, the title compound wasobtained.

Yield: 5.99 g (26.7 mmol) (76%)

H-NMR (CDCl3) δ:1.45 (9H, s), 3.46 (2H, dt), 3.51 (2H, t), 4.95 (1H, br)

Step 5: Synthesis of3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile

18.5 g (82.6 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in200 ml of DMF. 10.1 g (41.3 mmol) of 3-hydroxy-4-iodobenzonitrile and5.7 g (41.3 mmol) of potassium carbonate were added to the obtainedsolution, and they were stirred at 75° C. for 3 hours. After thetreatment with ethyl acetate as the extraction solvent in an ordinarymanner, the title compound was obtained.

Yield: 11.0 g (28.4 mmol) (69%)

H-NMR (CDCl3) δ:1.46 (9H, s), 3.62 (2H, dt), 4.12 (2H, t), 7.02 (2H,d),7.88 (2H, d).

Step 6: Synthesis of methyl2-acetylamino-3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylate

18.0 g (46.4 mmol) of3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile was dissolved in200 ml of DMF. 13.3 g (92.8 mmol) of methyl 2-acetamidoacrylate, 2.82 g(9.28 mmol) of tris(2-methylphenyl)phosphine, 1.04 g (4.64 mmol) ofpalladium acetate and 12.9 ml (92.8 mmol) of triethylamine were added tothe obtained solution, and they were stirred at 115° C. for 4 hours. Thesolvent was evaporated, and the obtained crude product was purified bythe silica gel column chromatography to obtain the title compound.

Yield: 12.2 g (30.3 mmol) (65%)

H-NMR (CDCl3) δ: 1.45 (9H, s), 2.03 (3H, s), 3.58 (2H, dt), 3.89 (3H,s), 4.18 (2H, t), 7.17 (1H, br), 7.23 (1H, d), 7.35-7.42 (2H, m)

Step 7: Synthesis of methyl2-acetylamino-3-[4-cyano-2-(2-(4-(1-methyl-2-imidazoline-2-yl)benzoylamino)ethoxy)phenyl]acrylatemono-trifluoroacetate

2.09 g (5.19 mmol) of methyl2-acetylamino-3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylatewas dissolved in 10 ml of 4 N solution of hydrogen chloride in dioxaneand 10 ml of dioxane, and the obtained solution was stirred at roomtemperature for 4 hours. The solvent was evaporated, and the residue wasdissolved in 10 ml of DMF. 1.37 g (5.71 mmol) of4-(1-methyl-2-imidazoline-2-yl)benzoic acid monohydrochloride, 1.10 g(5.71 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, 777 mg (5.71 mmol) of 1-hydroxybenzotriazole and 2.17 ml(15.6 mmol) of triethylamine were added to the obtained solution, andthey were stirred at room temperature overnight. The solvent wasevaporated, and the obtained crude product was subjected to the reversedphase high-performance liquid chromatography with silica gel chemicallybonded with octadodecyl group. After the elution with a mixed solutionof water and acetonitrile containing 0.1% (v/v) of trifluoroacetic acid,the intended fraction was freeze-dried to obtain the title compound.

Yield: 2.0 g (3.32 mmol) (64%)

H-NMR (DMSO-d6) δ:1.95 (3H, s), 3.06 (3H, s), 3.65 (3H, s), 3.70 (2H,dt), 3.76-4.13 (4H, m), 4.29 (2H, t), 7.20 (1H, s), 7.44 (1H, d), 7.63(1H, d), 7.69 (1H, d), 7.79 (2H, d), 8.06 (2H, d), 8.94 (1H, t), 9.69(1H, br)

Step 8: Synthesis of3-[4-amidino-2-(2-(4-(1-methyl-2-imidazoline-2-yl)benzoylamino)ethoxy)phenyl]-2-oxopropionicacid bistrifluoroacetate

2.0 g (3.32 mmol) of methyl2-acetylamino-3-[4-cyano-2-(2-(4-(1-methyl-2-imidazoline-2-yl)benzoylamino)ethoxy)phenyl]acrylatemono-trifluoroacetate was dissolved in a mixture of 25 ml of 4 Nsolution of hydrogen chloride in dioxane and 5 ml of ethanol, and theobtained solution was stirred at room temperature for 4 days. Thesolvent was evaporated, and the residue was dissolved in 20 ml ofethanol. 564 mg of ammonium carbonate was added to the obtainedsolution, and they were stirred at room temperature overnight. Thesolvent was evaporated, and the residue was dissolved in 10 ml of 6 Nhydrochloric acid, and the obtained solution was stirred at 80° C. for 4hours. The solvent was evaporated, and the obtained crude product wastreated in the same manner as that in step 7 in Example 51 to obtain thetitle compound.

Yield: 430 mg (0.633 mmol) (19%)

MS (ESI, m/z) 452 (MH+)

H-NMR (DMSO-d6) δ:3.05 (3H, s), 3.60-3.80 (2H, m), 3.78-4.40 (6H, m),4.31 (2H, t), 6.81 (1H, s), 7.37-7.49 (3H, m), 7.73-7.85 (3H, m),8.03-8.12 (3H, m), 9.05 (1H, t), 9.19-9.37 (5H, m)

EXAMPLE 52 Synthesis of3-[4-amidino-2-(2-((1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]-2-oxopropionicacid bistrifluoroacetate

Step 1: Synthesis of 1-(1-methylpyridinium-4-yl)piperidinecarboxylicacid

2.0 g (8.51 mmol) of ethyl 1-(4-pyridyl)-4-piperidinecarboxylate wasdissolved in 10 ml of methyl iodide, and the obtained solution wasstirred at 40° C. for 4 hours. The solvent was evaporated, and theobtained crude product was dissolved in 10 ml of concentratedhydrochloric acid, and the obtained solution was stirred at 70° C.overnight. The solvent was evaporated to obtain the title compound.

Yield: 1.2 g (5.48 mmol)

Step 2: Synthesis of methyl2-acetylamino-3-[4-cyano-2-(2-((1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]acrylate

1.16 g (2.88 mmol) of methyl2-acetylamino-3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylatewas dissolved in a mixture of 5 ml of 4 N solution of hydrogen chloridein dioxane and 5 ml of dioxane, and the obtained solution was stirred atroom temperature for-4 hours. The solvent was evaporated, and theresidue was dissolved in 10 ml of DMF. 700 mg (3.17 mmol) of1-(1-methylpyridinium-4-yl)piperidinecarboxylic acid, 1.47 g (3.17 mmol)of bromotripyrrolidinophosphonium hexafluorophosphate and 1.20 ml (8.64mmol) of triethylamine were added to the obtained solution, and theywere stirred at room temperature overnight. The solvent was evaporated,and the obtained crude product was treated in the same manner as that instep 7 in Example 51 to obtain the title compound.

Yield: 710 mg (1.41 mmol) (49%)

H-NMR (DMSO-d6) δ:1.47-1.68 (2H, m), 1.76-1.89 (2H, m), 1.96 (3H, s),2.53-2.64 (1H, m), 3.13-3.30 (2H, m), 3.44 (2H, dt), 3.70 (3H, s), 3.88(3H, s), (4H, m), 7.18 (1H, br), 7.22 (2H, d), 7.43 (1H, d), 7.58 (1H,br), 7.69 (1H, d), 8.10 (1H, t), 8.21 (2H, d), 9.69 (1H, br)

Step 3: Synthesis of3-[4-amidino-2-(2-((1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]-2-oxopropionicacid bistrifluoroacetate

710 mg (1.41 mmol) of methyl2-acetylamino-3-[4-cyano-2-(2-((1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl)amino)ethoxy)phenyl]acrylatewas dissolved in a mixture of 10 ml of 4 N solution of hydrogen chloridein dioxane and 2 ml of ethanol, and the obtained solution was stirred atroom temperature for 4 dys. The solvent was evaporated, and the obtainedresidue was dissolved in 10 ml of ethanol. 239 mg of ammonium carbonatewas added to the obtained solution, and they were stirred at roomtemperature overnight. The solvent was evaporated, and the residue wasdissolved in 10 ml of 6 N hydrochloric acid, and the obtained solutionwas stirred at 80° C. for 4 hours. The solvent was evaporated, and theobtained crude product was treated in the same manner as that in step 7in Example 51 to obtain the title compound.

Yield: 30 mg (0.043 mmol) (3%)

H-NMR (DMSO-d6) δ:1.48-1.65 (2H, m), 1.76-1.88 (2H, m), 2.54-2.65 (1H,m), 3.13-3.28 (2H, m), 3.33-3.52 (3H, m), 3.89 (3H, s), 3.97-4.27 (3H,m), 6.78 (1H, s), 7.20 (2H, d), 7.34-7.48 (2H, m), 8.13-8.26 (3H, m),8.32 (1H, d), 9.15 (2H, br), 9.27 (2H, br)

EXAMPLE 53 Synthesis ofN-[2-(3-amidinophenoxy)-ethyl]-4-(3,4-dimethoxybenzoyl)benzamide

Step 1: Synthesis of methyl 4-(3,4-dimethoxybenzoyl)benzoate

2.1 g (15.72 mmol) of aluminum chloride, a solution of 2.39 g (12.02mmol) of monomethyl terephthalate chloride dissolved in 2 ml ofdichloromethane and 1.2 ml (9.25 mmol) of 1,2-dimethoxybenzene dissolvedin 2 ml of dichloromethane were added to 10 ml of dichloromethane, andthey were stirred overnight. The reaction solution was poured into 5 gof 1 N hydrochloric acid/ice. After the treatment with chloromethane asthe extraction solvent in an ordinary manner, the solvent wasevaporated, and the obtained residue was washed with ethyl acetate anddichloromethane to obtain-the title compound.

Yield: 1.3 g (4.33 mmol) (47%)

H-NMR (DMSO) δ:3.82 (3H, s), 3.87 (3H, s), 3.92 (3H, s), 7.08-7.14(1H,d), 7.28-7.34 (1H, d), 7.38-7.42 (1H, d), 7.78-7.84 (2H, d),8.08-8.14 (2H, d).

Step 2 Synthesis of 4-(3,4-dimethoxybenzoyl)benzoic acid

1.3 g (4.33 mmol) of methyl 4-(3,4-dimethoxybenzoyl)benzoate wasdissolved in 50 ml of ethanol. 7 ml of 1 N sodium hydroxide solution wasadded to the obtained solution, and they were stirred overnight. Thesolvent was evaporated, and the residue was washed with ethyl acetateand then filtered to obtain the title compound.

Yield: 0.9 g (3.14 mmol) (73%)

H-NMR (DMSO) δ:3.82 (3H, s), 3.87 (3H, s), 7.08-7.14 (1H, d),7.30-7.34(1H, d), 7.39-7.41 (1H, d), 7.76-7.82 (2H, d).8.06-8.12 (2H,d).

Step 3: Synthesis of 3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile

5.85 g (29 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in 100ml of dimethylformamide. 2.38 g (26.4 mmol) of 3-hydroxybenzonitrile,3.04 g (53 mmol) of potassium carbonate and 4.31 g (53 mmol) of sodiumiodide were added to the obtained solution, and they were stirred at 50°C. for 6 hours. After the treatment with ethyl acetate as the extractionsolvent in an ordinary manner, the obtained crude product was purifiedby the silica gel column chromatography to obtain the title compound.

Yield: 3.3 g (13.3 mmol) (51%)

H-NMR (CDCl3) δ:1.44 (1H, s), 3.55 (2H, dt), 4.05 (2H, t), 4.95 (1H,brs), 7.12 (1H, d), 7.14 (1H, s), 7.26 (1H, d), 7.38 (1H, t)

Step 4: Synthesis of 3-(2-aminoethoxy)benzonitrile monohydrochloride

1.41 g of 3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile was dissolvedin 20 ml of 4 N solution of hydrogen chloride in dioxane, and theobtained solution was stirred at room temperature for 2 hours. Thesolvent was evaporated, and the residue was suspended indichloromethane. The obtained suspension was filtered to obtainhydrochloride of the title compound.

Yield: 0.89 g (4.48 mmol) (83%)

Step 5: Synthesis ofN-[2-(3-cyanophenoxy)ethyl]-4-(3,4-dimethoxybenzoyl)benzamide

0.68 g (3.45 mmol) of 3-(2-aminoethoxy)benzonitrile monohydrochloridewas dissolved in 20 ml of N,N-dimethylformamide (dehydrated). 0.9 g(3.14 mmol) of 4-(3,4-dimethoxybenzoyl)benzoic acid, 0.47 g (3.45 mmol)of 1-hydroxybenzotriazole, 0.48 ml (3.45 mmol) of triethylamine and 0.66g (3.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride were added to the obtained solution, and they were stirredovernight. The solvent was evaporated, and the residue was treated withethyl acetate as the extraction solvent in an ordinary manner to obtainthe title compound.

Yield: 1.4 g (3.25 mmol) (94%)

H-NMR (CDCl3) δ:3.89-3.94 (2H, m), 3.94 (3H, s), 3.97 (3H, s), 4.18-4.24(2H, t), 6.67 (1H, br), 6.87-6.92 (1H, d).7.14-7.19 (2H, m), 7.20-7.44(3H, m), 7.48-7.50 (1H, d), 7.79-7.83 (2H, d), 7.86-7.92 (2H, d).

Step 6: Synthesis ofN-[2-(3-amidinophenoxy)ethyl]-4-(3,4-dimethoxybenzoyl)benzamide

0.5 g (1.16 mmol) ofN-[2-(3-cyanophenoxy)ethyl]-4-(3,4-dimethoxybenzoyl)benzamide wasdissolved in 10 ml of N,N-dimethylformamide (dehydrated). 0.21 g (2.32mmol) of sodium hydrogensulfide dihydrate and 0.24 g (1.16 mmol) ofmagnesium chloride hexahydrate were added to the obtained solution undercooling with ice, and they were stirred at room temperature for 2.5hours. After the treatment with ethyl acetate as the extraction solventin an ordinary manner, the solvent was evaporated, and the obtainedcrude product was dissolved in 20 ml of acetone. 0.56 ml (9.0 mmol) ofmethyl iodide was added to the solution, and they were refluxed for 3hours. The solvent was evaporated, and the obtained crude product waswashed with ethyl acetate. After the filtration, the obtained crystalswere dissolved in 10 ml of methanol. 155 mg (2.0 mmol) of ammoniumacetate was added to the obtained solution, and they were stirred for 3hours. The solvent was evaporated, and the residue was treated in thesame manner as that in step 7 in Example 51 to obtain the titlecompound.

Yield: 160 mg (0.285 mmol) (25%)

MS (ESI,m/z) 448 (MH+)

H-NMR (DMSO) δ:3.68-3.75 (2H,q), 3.82 (3H, s), 3.87 (3H, s), 4.21-4.29(2H, t), 7.09-7.13 (1H, d), 7.29-7.43 (5H, m), 7.50-7.58 (1H, t),7.75-7.80 (2H, d), 7.98-8.04 (2H, d), 8.95-9.00 (1H, t), 9.10 (2H, s),9.30 (2H, s).

EXAMPLE 54 Determination of Activity of Inhibiting the ActivatedBlood-coagulation Factor X

130 μl of 100 mM tris hydrochloride buffer adjusted to pH 8.4 was addedto 10 μl of an aqueous solution of a compound to be tested. Then 10 μlof a 0.5 unit/ml solution of activated human blood coagulation factor X(a product of Enzyme Research Co.) in tris hydrochloride of pH 8.4 wasadded to the resultant mixture. After the incubation at room temperaturefor 10 minutes, 50 μl of a solution ofN-benzoyl-L-isoleucyl-L-glutamyl-glycyl-L-arginyl-P-nitroanilidehydrochloride (a product of Peptide Institute, Inc.) adjusted to 0.8 mMwith tris hydrochloride (pH 8.4) was added thereto. The absorbance wasdetermined and then the initial reaction rate was determined. A controlwas prepared in the same manner as that described above except that thesolution of the compound to be tested was replaced with 10 μl of trishydrochloride buffer adjusted to pH 8.4. The absorbance was determinedwith MICROPLATE READER Model 3550-UV (a product of BIO RAD) at a wavelength of 405 nm at intervals of 15 seconds for 16 minutes. The negativelogarithm (pIC₅₀) of a concentration of the test compound which inhibits50% of the activity (initial rate) of the activated blood coagulationfactor X in the absence of the test compound was determined, andemployed as the index of the activity of inhibiting activated bloodcoagulation factor X.

The activities, of inhibiting activated blood coagulation factor X, ofrepresentative compounds are shown in Table 1 given below.

EXAMPLE 55 Determination of Thrombin-inhibiting Activity

130 μl of 100 mM tris hydrochloride buffer adjusted to pH 8.4 was addedto 10 μl of an aqueous solution of a test compound. Then 10 μl of asolution of human thrombin (a product of SIGMA Co.) adjusted to 2units/ml with tris hydrochloride buffer of pH 8.4 was added to theresultant mixture. After the incubation at room temperature for 10minutes, 50 μl of a solution ofD-phenylalanyl-L-pipecolyl-L-arginyl-P-nitroanilide dihydrochloride(S-2238; a product of Daiichi Kagaku Yakuhin Co.) adjusted to 0.4 mMwith tris hydrochloride buffer of pH 8.4 was added thereto. Theabsorbance was determined and then the initial reaction rate wasdetermined. A control was prepared in the same manner as that describedabove except that the solution of the compound to be tested was replacedwith 10 μl of tris hydrochloride buffer adjusted to pH 8.4. Theabsorbance was determined with MICROPLATE READER Model 3550-UV (aproduct of MIO RAD) at a wave length of 405 nm at intervals of 15seconds for 16 minutes. The negative logarithm (pIC₅₀) of aconcentration of the test compound which inhibits 50% of the activity(initial rate) of the thrombin in the absence of the test compound wasdetermined, and employed as the index of the activity of inhibitingthrombin.

The activities, of inhibiting thrombin, of representative compounds areshown in Table 1 given below.

EXAMPLE 56 Determination of Blood Anticoagulating Activity

The blood anticoagulating activity was determined by a prothrombin time(PT) determination method. The PT was determined as follows: The bloodwas taken from healthy people. 3.8% aqueous trisodium citrate solutionwas added to the blood in a volume ratio of 1:10. The blood plasma wasseparated by the centrifugation. 5 μl of DMSO solution containing a testcompound was added to 45 μl of the blood plasma. After the incubation atroom temperature for 2 minutes, a test tube containing the blood plasmasolution was placed in Sysmex CA-3000 fully automatic blood coagulationdetermination device (a product of Toa Medical Electronics Co., Ltd.),and incubated at 37° C. for 3 minutes. 100 μl of Sysmex PT II (rabbitbrain tissue thromboplastin, 13.2 mM calcium chloride; a product of ToaMedical Electronics Co., Ltd.) was fed into the test tube. PT wasautomatically determined with the device. A sample containing 5 μl ofDMSO in place of the solution of the test compound was used as thecontrol. The negative logarithm (PT2) of the concentration of the testcompound which elongated PT of the control to the twice as long wasdetermined, and employed as the index of the blood anticoagulatingactivity.

TABLE 1 Activity of inhibiting Thrombin- activated blood coagulationinhibiting activity factor X (pIC₅₀) (pIC₅₀) Compd. of Ex. 2 7 <3.0Compd. of Ex. 4 7.5 <3.0 Compd. of Ex. 5 7.2 5.2 Compd. of Ex. 6 7.4<3.0 Compd. of Ex. 8 7 <3.0 Compd. of Ex. 9 7 5.5 Compd. of Ex. 10 7.4<3.0 Compd. of Ex. 13 7.6 <3.1 Compd. of Ex. 14 7.8 <4.0 Compd. of Ex.15 8 <4.0 Compd. of Ex. 26 7.8 <4.0 Compd. of Ex. 28 7.8 <4.0 Compd. ofEx. 29 7.9 <4.0 Compd. of Ex. 37 7.3 <4.0 Compd. of Ex. 38 7 3.3 Compd.of Ex. 42 7.2 <3.3 Compd. of Ex. 43 7.8 <4.0 Compd. of Ex. 51 8.1 4.3Compd. of Ex. 52 7.1 4.2

It is apparent from the results that the benzamidine derivatives of thepresent invention have a specifically high activity of inhibiting theactivated blood coagulation factor X, and they exhibit a highanticoagulating activity based on this inhibiting activity.

The structural formulae of the compounds of the present inventiondescribed in the Examples are given below.

Effect of the Invention

The anticoagulant containing a compound of the present invention or asalt thereof as the active ingredient has a blood-coagulation inhibitingeffect based on the excellent effect of inhibiting activatedblood-coagulation factor X. Therefore, the compounds of the presentinvention are usable as agents for preventing or treating diseases suchas cerebrovascular disorders such as cerebral infarction, cerebralthrombosis, cerebral embolism, transient ischemic attack (TIA) andsubarachnoidal hemorrhage (vasospasm); ischemic heart diseases such asacute and chronic myocardial infarction, unstable angina and coronarythrombolysis; pulmonary vascular disorders such as pulmonary infarctionand pulmonary embolism; peripheral obliteration; deep vein thrombosis;disseminated intravascular coagulation syndrome; thrombus formationafter an artificial blood vessel-forming operation or artificial valvesubstitution; re-occlusion and re-stenosis after a coronarybypass-forming operation; re-occlusion and re-stenosis afterreconstructive operation for the blood circulation such as percutaneoustransluminal coronary angioplasty (PTCA) or percutaneous transluminalcoronary recanalization (PTCR); and thrombus formation in the course ofthe extracorporeal circulation.

What is claimed is:
 1. A composition comprising: a) one or morebenzamidine compounds of the following formula (1-1) or apharmaceutically acceptable salt thereof:

wherein L represents an organic group of any of the following formulae(2) to (5):

wherein W in formulae (2), (3) and (5) represents a hydrogen atom, analkyl group having 1 to 6 carbon atoms, an aryl group having 4 to 10carbon atoms or an aralkyl group having 5 to 12 carbon atoms, one of Dand D′ in formula (3) represents a bond to Y in general formula (1-1)and the other represents a hydrogen atom, X in formula (2) represents ahydrogen atom, carboxyl group, an alkoxycarbonyl group having 1 to 3carbon atoms, an alkyl group having 1 to 3 carbon atoms, whichoptionally has a substituent(s), or a benzyl group which optionally hasa substituent(s); wherein the substituent(s) is selected from the groupconsisting of a carboxyl group, alkoxycarbonyl groups having 2 to 8carbon atoms, alkylsulfonyloxy groups having 1 to 6 carbon atoms,piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbonatoms, alkoxycarbonylpiperidyloxy groups having 7 to 14 carbon atoms,piperidylalkyl groups having 6 to 8 carbon atoms,iminoalkylpiperidylalkyl groups having 7 to 11 carbon atoms,alkoxycarbonylpiperidylalkyl groups having 8 to 15 carbon atoms,pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbonatoms, amidino group, mono- or dialkylamidino groups having 2 to 7carbon atoms, hydroxyl group, halogeno groups, indolyl group and alkylgroups having 1 to 3 carbon atoms, X and W in formula (2) may be bondedtogether to form a ring and, in this case, —W—X— represents an ethylenegroup, trimethylene group or tetramethylene group, when L is an organicgroup of any of formulae (2) to (4), V₁ represents a hydrogen atom,benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl, piperazinecarbonyl,cinnamoyl, piperidinecarbonyl, 4-methylthiazole-5-carbonyl phenylacetyl,phenylthiocarbonyl or benzimidoyl group, which optionally has asubstituent(s), or an alkanesulfonyl group having 1 to 6 carbon atoms,which optionally has a substituent(s), and when L is an organic group offormula (5), V₁ represents an aryl group having 4 to 10 carbon atoms,which optionally has a substituent(s), when L is an organic group of anyof formulae (2) to (5) and V₁ has a substituent(s); wherein thesubstituent is selected from the group consisting of carboxyl group,alkoxycarbonyl groups having 2 to 7 carbon atoms, carbamoyl group, mono-or dialkylcarbamoyl groups having 2 to 7 carbon atoms, amidino group,mono- or dialkylamidino groups having 2 to 7 carbon atoms, acyl groupshaving 1 to 8 carbon atoms, halogeno groups, amino group, mono- ordialkylamino groups having 1 to 6 carbon atoms, arylamino groups having4 to 6 carbon atoms, alkoxycarbonylamino groups having 2 to 7 carbonatoms, aminoalkyl groups having 1 to 3 carbon atoms, mono- ordialkylaminoalkyl groups having 2 to 7 carbon atoms,N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon atoms,piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbonatoms, alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms,pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbonatoms, hydroxycarbonylalkyl groups having 2 to 7 carbon atoms,alkoxycarbonylalkyl groups having 3 to 8 carbon atoms,hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms,alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl groupshaving 4 to 10 carbon atoms, arylalkenyl groups having 6 to 12 carbonatoms, alkoxyl groups having 1 to 10 carbon atoms, nitro group,trifluoromethyl group, alkyl groups having 3 to 8 carbon atoms,arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl groups having5 to 12 carbon atoms, piperazinecarbonyl group,iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms,piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups having 6to 9 carbon atoms, piperidylalkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms,piperidylidenealkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms, guanidinogroup, dialkylguanidino groups having 3 to 5 carbon atoms, phosphonogroup, dialkoxyphosphoryl groups having 2 to 9 carbon atoms,monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms,trialkylamidino groups having 4 to 7 carbon atoms, dialkoxybenzoylgroups having 9 to 13 carbon atoms, 1-alkylpyridinio groups having 6 to9 carbon atoms and groups of the following formulae:

wherein A in formulae (6) and (7) represents a halogeno group, and B informulae (8) and (9) represents a hydrogen atom, an alkyl group having 1to 6 carbon atoms, a halogeno group or amino group, Y represents any offollowing formulae (10) to (16):

wherein n in formulae (10) and (11) represents an integer of 0 to 2, R¹in formula (16) represents a hydrogen atom, a hydroxycarbonylalkyl grouphaving 2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8carbon atoms or a hydroxycarbonylalkenyl group having 3 to 7 carbonatoms, Z₁ represents a group of any of following formulae (17) to (24):

wherein m in formulae (17), (19), (21) and (23) represents an integer of0 to 3, R² in formulae (17), (18) and (24) represents a hydroxyl group,an alkoxyl group having 1 to 5 carbon atoms, trifluoromethyl group,amino group or a mono- or dialkylamino group having 1 to 6 carbon atoms,R³ in formula (19) represents a hydrogen atom, an alkyl group having 1to 6 carbon atoms or acetyl group, R⁴ in formulae (20) to (23)represents hydrogen atom or an alkyl group having 1 to 6 carbon atoms,R⁵ in formulae (22) and (23) represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms, and R⁶ in formula (24) represents ahalogeno group; and b) a pharmaceutically acceptable carrier.
 2. Thecomposition according to claim 1, wherein, in general formula (1-1), Lrepresents an organic group of formula (2), W represents a hydrogen atomand X represents a hydrogen atom, carboxymethyl group orethoxycarbonylmethyl group.
 3. The composition according to claim 1,wherein, in general formula (1-1), Y represents an organic group ofgeneral formula (10) and n represents an integer of 1 or
 2. 4. Thecomposition according to claim 1, wherein V₁ in general formula (1-1)represents 1-acetimidoyl-4-piperidyloxybenzoyl group,1-(4-pyridyl)piperidine-4-carbonyl group,1-(2,3,5,6-tetrafluoropyridine-4-yl)piperidine-4-carbonyl group,1-(3,5-dichloropyridine-4-yl)-piperidine-4-carbonyl group,1-(6-chloropyridazine-3-yl)-piperidine-4-carbonyl group,1-(pyridazine-3-yl)piperidine-4-carbonyl group,1-(2-chloropyrimidine-4-yl)-piperidine-4-carbonyl group,1-(pyrimidine-4-yl)-piperidine-4-carbonyl group,1-(4-pyridine-4-ylmethyl)-piperidine-4-carbonyl group,1-(4-pyridine-4-carbonyl)-piperidine-4-carbonyl group or4-methyl-2-pyridyl-4-yl-thiazole-5-carbonyl group.
 5. The compositionaccording to claim 1, wherein, Z₁, in general formula (1-1) represents acarboxyethyl group, ethoxycarbonylethyl group, carboxyvinyl group;ethoxycarbonylvinyl group, carbamoylethyl group, carbamoylvinyl,carboxyl group, ethoxycarbonyl group, methoxycarbonyl group, sulfoethylgroup, sulfovinyl group, phosphonovinyl group, diethoxyphosphorylvinylgroup, monoethoxyhydroxyphosphorylvinyl group, sulfonoethyl group,diethoxyphosphorylethyl group, monoethoxyhydroxyphosphorylethyl group,hydroxymethyl group, hydroxypropyl group or acetoxymethyl group.
 6. Thecomposition according to claim 1, wherein, in general formula (1-1), Lrepresents an organic group of formula (2), Y represents an organicgroup of formula (10), V₁ represents 1-acetimidoyl-4-piperidyloxybenzoylgroup or 1-(4-pyridyl)-piperidine-4-carbonyl group, and Z₁ represents acarboxyethyl group, ethoxycarbonylethyl group, sulfoethyl group,hydroxymethyl group or hydroxypropyl group.
 7. The composition accordingto claim 1, wherein, in general formula (1-1), L represents an organicgroup of formulae (2) to (4), and Y represents an organic group offormulae (10) to (13).
 8. The composition according to claim 1, wherein,in general formula (1-1), when L represents an organic group of any offormulae (2) to (4), V₁ represents a hydrogen atom, benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl, cinnamoyl, piperidinecarbonyl,phenylacetyl, phenylthiocarbonyl or benzimidoyl group which optionallyhas a substituent(s), or an alkanesulfonyl group, having 1 to 6 carbonatoms, which optionally has a substituent(s); and when L is an organicgroup of formula (5), V₁ represents an aryl group, having 4 to 10 carbonatoms, which optionally has a substituent(s), when L represents anorganic group of any of formulae (2) to (5), the substituents of V₁include a carboxyl group, alkoxycarbonyl groups having 2 to 7 carbonatoms, carbamoyl group, mono- or dialkylcarbamoyl groups having 2 to 7carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, amidinogroup, mono- or dialkylamidino groups having 2 to 7 carbon atoms, acylgroups having 1 to 8 carbon atoms, halogeno groups, amino group, mono-or dialkylamino groups having 1 to 6 carbon atoms, arylamino groupshaving 4 to 6 carbon atoms, alkoxycarbonylamino groups having 2 to 7carbon atoms, aminoalkyl groups having 1 to 3 carbon atoms, mono- ordialkylaminoalkyl groups having 2 to 7 carbon atoms,N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon atoms,piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbonatoms, alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms,pyrrolidinyloxy group, iminoalkylpyrrolidinyloxy groups having 5 to 9carbon atoms, alkoxycarbonylpyrrolidinyloxy groups having 7 to 13 carbonatoms, hydroxycarbonylalkyl groups having 2 to 7 carbon atoms,alkoxycarbonylalkyl groups having 3 to 8 carbon atoms,hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms,alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl groupshaving 4 to 10 carbon atoms, arylalkenyl groups having 6 to 12 carbonatoms, alkoxyl groups having 1 to 10 carbon atoms, nitro group,trifluoromethyl group, alkyl groups having 3 to 8 carbon atoms,arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl groups having5 to 12 carbon atoms, piperazinecarbonyl group,iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms,piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups having 6to 9 carbon atoms, piperidylalkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms,piperidylidenealkyl groups having 6 to 9 carbon atoms,iminoalkylpiperidylidenealkyl groups having 8 to 12 carbon atoms,guanidino group, dialkylguanidino groups having 3 to 5 carbon atoms,phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atoms ormono alkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms, Yrepresents any of formulae (10) to (16), n in formulae (10) and (11)represents an integer of 1 or 2, and Z₁ represents a group of formula(17) or (18) wherein m represents an integer of 1 to 3, and R²represents hydroxyl group, an alkoxyl group having 1 to 5 carbon atoms,amino group or a mono- or dialkylamino group having 1 to 6 carbon atoms.9. The composition according to claim 8, wherein, in general formula(1-1), L represents an organic group of formula (2), W represents ahydrogen atom and X represents a hydrogen atom, carboxymethyl group orethoxycarbonylmethyl group.
 10. The composition according to claim 8,wherein, in general formula (1-1), Y represents an organic group ofgeneral formula (10) and n represents an integer of
 1. 11. Thecomposition according to claim 8, wherein, V₁ in general formula (1-1)represents 1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)piperidine-4-carbonyl group.
 12. The composition accordingto claim 8, wherein, Z₁ in general formula (1-1) represents acarboxyethyl group, etboxycarbonylethyl group, carboxyvinyl group,ethoxycarbonylvinyl group, carbamoylethyl group or carbamoylvinyl group.13. The composition according to claim 8, wherein, in general formula(1-1), L represents an organic group of formula (2), Y represents anorganic group of formula (10), V₁ represents1-acetimidoyl-4-piperidyloxybenzoyl group or1-(4-pyridyl)-piperidine-4-carbonyl group, and Z₁ represents acarboxyethyl group, etboxycarbonylethyl group or carbamoylethyl group.14. A composition comprising: a) one or more benzamidine compounds offollowing formula (1-2) or a pharmaceutically acceptable salt thereof:

wherein Z₁₁ represents carboxyethyl group, ethoxycarbonylethyl group,hydroxymethyl group or hydroxypropyl group, and E represents anoil-soluble organic group; and b) a pharmaceutically acceptable carrier.15. A composition comprising: a) one or more benzamidine compounds ofthe formula: wherein:

Z₁₁ is carboxyethyl, ethoxycarbonylethyl, hydroxymethyl orhydroxypropyl; E is an oil-soluble organic group of the formula—Y—L—V₁—, wherein L is an organic group of the formula (2):

wherein W is hydrogen, C₁-C₆ alkyl, C₄-C₁₀ aryl or C₅-C₁₂ aralkyl; and Xis hydrogen, carboxyl, alkoxycarbonyl having 1 to 3 carbon atoms, alkylof 1 to 3 carbon atoms which is optionally substituted, benzyl which isoptionally substituted, or X and W are bonded together to form a ring,wherein —W—X— is selected from the group consisting of ethylene,trimethylene and tetramethylene; Y is an organic group of the formula(10):

wherein n is an integer of 0 to 2; and V₂ is1-acetamidoyl-4-piperidyloxybenzoyl or1-(4-pyridyl)piperidine-4-carbonyl; and b) a pharmaceutically acceptablecarrier.
 16. The composition according to claim 15, wherein, in generalformula (1-2), L represents an organic group of formula (2), Wrepresents a hydrogen atom, X represents a hydrogen atom, V₂ represents4-(3,4-dimethoxybenzoyl)benzoyl group,1-(1-methylpyridinium-4-yl)piperidine-4-carbonyl group or4-(1-methyl-2-imidazoline-2-yl)benzoyl group, and Z₂ represents ahydrogen atom or 2-carboxy-2-oxoethyl group.
 17. The compositionaccording to claim 15, wherein, in general formula (1-2), L representsan organic group of formula (2), W represents a hydrogen atom, Xrepresents a hydrogen atom, V₂ represents4-(1-methyl-2-imidazoline2-yl)benzoyl group, and Z₄ represents2-carboxy-2-oxoethyl group.